Wailea, Maui, Hawaii - The best beaches, resorts, food, diving, and golf on an island that is surely as close to paradise as God will ever allow in this life. If you've never been to Hawaii, all I can say is: GO. Worth every penny, even if you had to save for 3 or 4 years to get there.
Key West Florida - Take all the good parts of New Orleans, float 'em out on a cruise ship, dump on some sand, point it toward the sunset, and then ride through on a scooter. Oh, don't forget to add daquiris. A lot of them. Hey, if you don't like it, you can always escape to Cuba, it's only 90 miles away.
Hot-lanta - If you can't find something to do there, you need to just put yourself out of your misery.
(Tie)
Tampa, FL - Very much like Atlanta, but a little smaller and on the coast. Very young, tons to do, tons to eat, lots of history. Worth the trip to "people watch" in Ybor City alone. Oh, and don't forget Legends Field and the Pirate Ship. Also, home to some of the most famous "adult venues" in the country (if you're into that sort of thing)
Charleston, SC - Best food I've ever had. Throw in the history, coastline, and entertainment, and you've got yourself one heckuva weekend vacation spot.
New Orleans, LA - Not NEARLY as dirty or crowded as people make it out to be, unless it's Mardi Gras, Jazz Fest, or New Years. Incredible dining, 5-star accommodations, an insane selection of music, art, gambling, and history. Have not been back since the 'cane, but am very eager to contribute to the rebuilding process with a pilgrimmage.
Portland, OR - don't listen to 2345, Oregon is a BEAUTIFUL place with tons to do. Life is different in the northwest. Music, skiing, dining, breweries, wineries, rainforests, and some very unique coastline makes this state a "must visit."
And, of course, Knox-vegas. The entire city is painted orange and white, great boating, biking, hiking and golf are nearby, perhaps more good restaurants "per capita" than anywhere else in the world, and it just feels "like home," dadgummit. I came back to raise my family here, and so should you.
Others:
Negril, Jamaica - wow for the beaches and resorts
Seaside, FL - don't believe the negative vibes from Panama and Destin, the Emerald coast has the nicest beaches in the Eastern US
Washington, DC - you just have to go if you're an American. Go see the center of the world's political power, cry at the one place where men are SUPPOSED to, and prepare yourself to be amazed at the multicultural variety
Hilton Head, SC - Anyone say, Golf?
Miami, FL - Where the stars go to play. Take your wallet.