Day 1: Jacksonville to St. Augustine (38 miles)
Fly into JAX, then drive south along the coast to the oldest European settlement in America.
Lunch: Angie's Subs
Memorable sandwiches in a nondescript mini-mall popular with surfer types. 1436 Beach Blvd., Jacksonville Beach; 904/249-7827; lunch for two $15.
See: Castillo de San Marcos
Imposing 17th-century fort that makes a good jumping-off point for a walking tour of St. Augustine's historic downtown.
Snack: The Hyppo
Artisan ice pops made from seasonal ingredients (try the pineapple-cilantro) and modeled after Mexican paletas. 15 Hypolita St., St. Augustine; 904/217-7853; ice pops for two $7.
Dinner: The Floridian
Husband-and-wife team Jeff McNally and Genie Kepner put their own spin on trusted Southern favorites. Grab a bottle of biodynamic wine from the bar next door to pair with the shrimp and grits. 39 Cordova St., St. Augustine; 904/829-0655; dinner for two $40.
Stay: Casa Monica Hotel
Great Value Moorish-style grandeur in an 1888 property once owned by railroad tycoon Henry Flagler, who developed much of Florida's eastern coast. Doubles from $199.
Best Town Crawl: The Tasting Tours' Vittles and Vino ($76), a three-hour feast through the city's top restaurants and food shops.
Day Two: St. Augustine to Palm Beach (257 miles)
Next up on the road trip, two of Florida's greatest hits: a retro spring-break capital and the site where U.S. space history was made.
Breakfast: Casa Maya
This tiny spot serves Yucatecan dishes made with organic ingredients. Fuel up on the "huevos de Popeye" before hitting the road. 17 Hypolita St., St. Augustine; 904/217-3039; breakfast for two $20.
See: Daytona Beach
Swanky it's not, but the town is still worth a stop, if only to buy a $5 beach day pass and cruise along the hard-packed sand in your car at 10 mph.
See: Kennedy Space Center
NASA's former launch headquarters is guaranteed to fascinate.
Related: America's Warmest Vacation Resorts
Lunch: Jazzy's Mainely Lobster & Seafood Co.
No, you can never have too much fish in Florida, as evidenced by the crowd here. 210 N. Orlando Ave., Cocoa Beach; 321/613-3993; lunch for two $25.
Stay: Ritz-Carlton, Palm Beach
Seven-acre beachfront spread that's a welcome sight at the end of a long drive. Eau Spa is a design stunner; the reopened Angle restaurant has a Regency-meets-supper-club ambience. Doubles from $479.
T+L Tip: Right next to the Kennedy Space Center, Merritt Island National Wildlife Refuge has one of the east coast's most beautiful beaches: shell-strewn Playalinda.
Day Three: Palm Beach to Miami Beach (63 miles)
Start the day in Florida's old-guard enclave, then head to the ultimate luxury-shopping hub.
Shop: Palm Beach Area
Possibly the most rewarding place in the country to score designer thrift and secondhand couture. Two not to miss: Palm Beach Vintage (3623 S. Dixie Hwy., West Palm Beach; 561/718-4075), which carries beaded cocktail dresses, and Groovy Palm Beach (108 N. County Rd., Palm Beach; 561/628-9404) for Lilly Pulitzer and Pucci.
Shop: Trouser Shop
In ripe-for-discovery Delray Beach, this sartorial staple excels in preppy classics: snap up a pair of patch-madras pants or a custom cotton web belt cut off the roll while you wait. 439 E. Atlantic Ave., Delray Beach; 561/278-5626.
See: IGFA Fishing Hall of Fame & Museum
Just outside Fort Lauderdale and a must for any nature enthusiast. Grab lunch next door at the Islamorada Fish Co., an outpost of the Keys chainlet (it's housed, appropriately enough, in a Bass Pro Shop). 300 Gulf Stream Way, Dania Beach; 954/922-4212.
Stay: Quarzo Bal Harbour
Space is the draw at this recently opened property near the exclusive Bal Harbour Shops. (Look for Gucci, Prada, and Bottega Veneta, plus the excellent Books & Books.) Quarzo feels less like a hotel than a boutique apartment complex, with suites that top out at 1,800 square feet. 290 Bal Bay Dr., Bal Harbour; 305/222-7922; doubles from $350.
An Asian-inspired gastropub? Curiously, it works. Welcoming spot with a Brooklyn-esque vibe (hipsters with their parents). 1418 20th St., Miami Beach; 305/532-7555; dinner for two $90.
Day Four: Miami Beach to Islamorada (80 miles)
Welcome to the easy, breezy Florida Keys—no shoes required.
Breakfast: David's Café II
Order a café con leche from the walk-up window. Ccoffee for two $4.
Lunch: Shiver's BBQ
Roadside pit stop specializing in ribs smoked over hickory wood and slathered with house-made sauce. 28001 S. Dixie Hwy., Homestead; 305/248-2272; lunch for two $25.
Do: Holiday Isle Resort
Get out on the water by chartering a sportfishing excursion or renting a boat at this tiki-festooned marina. 84001 Overseas Hwy., Islamorada; 305/664-2321; two-hour boat rentals from $165.
Shop: Shell Shack
Candy and Mike Baker have been selling shells and curios for 40-plus years. 83005 Overseas Hwy., Islamorada; 305/664-9467.
See: History of Diving Museum
Passionately curated, with displays of vintage artifacts and underwater equipment. 82990 Overseas Hwy., Islamorada; 305/664-9737.
Stay: Casa Morada
Petite, well-styled boutique hotel with simple, whitewashed interiors. Doubles from $299.
Dinner: Lorelei Cabana Bar
Join the fishing guides for a bowl of conch chowder. 81924 Overseas Hwy., Islamorada; 305/664-2692; dinner for two $20.
Angler alert: more world-record fish have been caught in Islamorada than anywhere else on earth.
Related: Florida Keys Travel Guide
Day Five: Islamorada to Key West (81 miles)
At the road trip's end: the southernmost point of the continental United States.
Breakfast: Green Turtle Inn
Revamped 1940's diner with one of the best morning meals around (just try to resist the coconut French toast). 81219 Overseas Hwy., Islamorada; 305/664-2006; breakfast for two $20.
Do: Robbie's of Islamorada
Feeding the tarpon ($3 for a bucket of bait) off the dock of this water-sports center is a Keys rite of passage. 77522 Overseas Hwy., Islamorada; 305/664-9814.
Lunch: Seven Mile Grill
Just north of the Seven Mile Bridge, which connects Marathon to the Lower Keys. Order the grouper sandwich. 1240 Overseas Hwy., Marathon; 305/743-4481; lunch for two $25.
Shop: Isle Style
A true fashion oasis in souvenir-laden Key West: colorful women's wear and accessories that would look equally at home on the beaches of Malibu. 1204 Simonton St., Key West; 305/292-4000.
Stay: Casa Marina, a Waldorf Astoria Resort
Great Value Rita Hayworth and Gregory Peck are among the stars who once stayed at this revamped 1920 compound, another product of Henry Flagler's bold vision. Doubles from $199.
See: Key West Sunset
The main event in town. You could brave the carnival-like Mallory Square, where the rowdy Sunset Celebration involves sword swallowers and fortune-tellers. Or you could sit back with a cocktail at Casa Marina's Sun Sun beach bar and toast the day's end in a more civilized fashion.
Dinner: Pepe's Café
Atmospheric little shack that's the oldest restaurant (est. 1909) in Key West. Head here primarily for the Key lime pie—pleasingly tart, garnished with whipped cream, and served in a bowl. 806 Caroline St., Key West; 305/294-7192; pie for two $8.
Spotlight: Florida Neighborhood Report
Eclectic, artsy Wynwood is Miami's most unexpected cultural hot spot—and a good contrast to the glossy south beach scene.
The Northwest Second Avenue main drag is packed with cutting-edge galleries and high-design restaurants. The best way to take it all in? Hop on a Vespa for a Roam Rides guided tour (888/760-7626; $125).
Butter Gallery: Contemporary art space whose eye-catching exterior (a wall of painted eyeballs) could easily pass for a nightclub. 2301 N.W. Second Ave.; 305/303-6254.
Cafeina Wynwood Lounge: Gathering spot that serves as a brunch destination, gallery, and late-night lounge. 297 N.W. 23rd St.; 305/438-0792; brunch for two $22.
Joey's Italian Café: The neighborhood's flagship restaurant. You can't go wrong, whether you sit indoors or on the action-packed patio. Dinner for two $30.
Lester's: Coffee and wine bar created by a former artist and chock-full of obscure books and literary journals. 2519 N.W. Second Ave.; 305/456-1784; drinks for two $11.
Panther Coffee: Its orange, green, and white façade is as vibrant as a Missoni print, but the paint job isn't the only thing that's buzzing at this temple to specialty java. 2390 N.W. Second Ave.; 305/677-3952; coffee for two $5.
Plant the Future: Argentina-born Paloma Teppa eschews traditional cut flowers in favor of sculptural compositions of orchids, succulents, and even butterfly cocoons. 2511 N.W. Second Ave.; 305/571-7177.
Wynwood Kitchen & Bar: Chef Miguel Aguilar puts his stamp on the Latin-inflected menu, but the art-filled interiors are as much of a draw as the food. 2550 N.W. Second Ave.; 305/722-8959; dinner for two $70.
Wynwood Walls: It's part free outdoor gallery, part Disney World for grown-ups at this open-air art park next to Wynwood Kitchen & Bar. —Eleni N. Gage
Side Trip: On the Gulf Coast
World-class art comes to this beach-blessed stretch of western Florida, already known for its wildlife. Here, four places not to miss.
Gasparilla Island: Sea turtle nesting is up on this barrier isle, beloved for its circa 1890 lighthouse. Naturalists are hoping for even more turtle nests in the 2012 season, which runs from May to October. Try your luck at spotting hatchling tracks—made during their break toward the sea—on a beach walk in Gasparilla Island State Park (880 Belcher Rd., Boca Grande).
St. Petersburg: The new Chihuly Collection (400 Beach Dr. N.E.; 727/822-7872) is the world's first permanent exhibition space for the work of American sculptor Dale Chihuly.
The Dalí Museum (1 Dali Blvd.; 727/823-3767), which houses more than 2,000 paintings by the surrealist icon, recently relocated to a $36 million glass-and-concrete building designed by global architectural firm HOK.
Sanibel Island: Bucolic nature meets 21st-century technology at J. N. "Ding" Darling National Wildlife Refuge. It just unveiled an iNature Trail, the first of its kind in the United States. Visitors can scan smart-phone codes along hiking paths to access online videos for more in-depth information. —Lindsey Olander
Great Value Boca Raton Interior designer Jane Dillon has revamped the 244-room tower at the Boca Raton Resort & Club (501 E. Camino Real; 888/543-1277; bocaresort.com; doubles from $219). Look for headboards in raw-silk tweed and floors accented with David Hicks–like geometric rugs.
Great Value Sunny Isles Beach Neomi's Grill, the restaurant at the Trump International Beach Resort (18001 Collins Ave.; 866/628-1197; trumpmiami.com; doubles from $219), debuts a modern new look courtesy of Michael Wolk Design Associates, which also refreshed the lobby.
Bal Harbour Scheduled to open in 2012, the St. Regis Bal Harbour Resort & Residences (9703 Collins Ave.; 877/787-3447; stregis.com; doubles from $850) houses Jean-Georges Vongerichten's first Florida outpost, J&G Grill.
Miami One of the best spas in town ups the ante with the addition of a beauty-focused VIP treatment suite. The Mandarin Oriental, Miami (500 Brickell Key Dr.; 800/526-6566; mandarinoriental.com; doubles from $479), is also introducing a menu of pampering options exclusive to the space.
Miami Beach Lenny Kravitz. Philippe Starck. José Andrés. They're just three of the heavy hitters involved in the SLS Hotel South Beach (slshotels.com), slated to open next spring. It will be Starck's first Miami design work since the Delano.
Miami Beach Polish-born designer Anna Busta unveils her new look for guest rooms at the W South Beach Hotel & Residences (2201 Collins Ave.; 877/946-8357; whotels.com; doubles from $709) early next year. —Lindsey Olander