We drove from Key Largo to Key West for a daytrip when we checked out of our Largo hotel.
We were on a tour and booked into another hotel in Miami, so went Key Largo to Key West then all the way back to Miami.
Wow, what a long day that was! The big problem is speed limits. In the UK we would happily sit at 70mph+ and do the journey in good time, but there are so many different speed limits through the Keys (40mph at times) that it takes ages.
We had a State Trooper following us all the way back so had to stick to the limits, otherwise would have put my foot down a bit more.
There is no way I would really want to do it from Orlando to be honest.
We stayed at a few resorts on the Gulf Coast on our way down (Clearwater, St Petes, Sarasota & Naples) and the drive from Naples to Key Largo was an enormous journey right through the Everglades. Fabulous scenery, but exhausting!