One thing to consider is a trip from Fort Myers Beach aboard the Key West Express, a very large hydrofoil. This ship can accomodate 511 passengers! The ride from Fort Myers to Key West takes three hours(give or take, based on the seas). Departure from Fort Myers Beach is at Salty Sam's Marina. Arrival in Key West is at the northern pier, just about a block from the head of Duvall Street. Round trip cost from Fort Myers is approximately $120 per person.

Main deck seating is enclosed in a vast cabin, with many, many banquettes. Breakfast and lunch/dinner fare is offered, and not too pricy. A full service bar opens when the ship reaches federal waters. Hold onto your hat if you go up top to the open air seating. The speed of the ship is accentuated by the stiff breeze in your face.

A word of advice when planning to board for departure from Key West: get to the pier at least 90 minutes ahead of sailing time. Boarding is "first-come, first served". You'll be competing for a nice seat with an army of overnighters from the island who are bringing luggage back with them. No luggage stowage aboard, so suitcases rest everywhere in the main cabin.

Key West Express also motors to the island from a port located on Marco Island.  

http://www.seakeywestexpress.com/boat...

Other ways 

Most expensive:
Fly direct into Key West. Continental, Delta, U.S. Air Ways and American Airlines fly into Key West International Airport (EYW). Book early because ‘in season’  (Oct – May) can be a real bear to find a flight. Also remember, on most flights, there will be strict luggage restrictions!  Key West has one runway oriented at 9 / 27 (meaning it runs due East and West – 90 degrees and 270 degrees) with a total length of 4801 feet. That means small, light planes only.

Common:
Fly / Drive combo: Fly into Miami International and rent a car to make the 3.5 – 4 hour drive. Make your rental one-way. Turn it in at the Key West airport and make another one-way rental back to MIA when you depart.  The down-side here is the time. Allow plenty to pick your car up at MIA… At least an hour and allow at least the same to return it. The drive itself should be done at least once but after that, it’s very long. Very boring and very tiresome. The Overseas Highway is patrolled by the Florida Highway Patrol as well as the Monroe County Sheriffs Department. The speed limit bounces between 45 and 55 on a two-lane road. After a week of fun and sun, the drive back to MIA is like walking three miles on broken glass. This is especially true if you gave Key West a proper good-bye the night before.

Keys Shuttle
There is another option with Keys shuttle. They run nine seat vans up and back. It’s basic transportation and at the time of this writing, they charge $80.00 per person, one-way plus tax from Miami.  www.keysshuttle.com