We did an overnight trip to Key West, FL, and driving took us about 3.5 hours each way. We were surprised to find that services, such as fuel and food, were plentiful all along the route. I would suggest fueling up at or before Key Largo, or you'll pay more.
We stayed in the Comfort Inn, which was a great place to stay for the price, but a short drive from the famed Duval Street. (A Doubletree Resort was our first choice, but it was closed due to some problem.) We ate at a Cuban eatery for lunch and had pork sandwiches, which were great. The sunset booze cruise aboard a schooner was worth the money, and we even saw the "green flash" at sunset. Shopping along Duval Street was fun. I wish we would have stopped at Sloppy Joe's, an old Hemingway hangout. You must see the Hemingway House (http://www.hemingwayhome.com/), a very interesting tour and a great old house.
There were lots of things to do, and we plan to take a trip back to hit all the sights and lie on the beach. Ride the trolley for a great guided tour with facts and history about Key West.