I'd get a comparative air fare & rental car rates from the 2 airports close by - Ft Lauderdate & Miami.

Depending on your origination and airlines, one airport might offer a better pricing than the other. And sometimes combining 2 different airports close by might give you better fare and/or more options in schedule. So here is an example of possible routing for fares:
1. Your City <->Miami (rt)
2. Your City <->Ft Lauderdale (rt)
3. Your City ->Ft Lauderdale and return by Miami -> your city
4. Your city -> Miami and return by Ft Lauderdale -> your city
5. Your City -> Miami or Ft Lauderdate and return from Key West (this most likely will cost you more but may save you time and rental car since you don't have to drive to Key West Round trip), although I personally like to drive to Key West RT to get different views from both directions.

Same with rental cars. I found out from a previous Key West trip that "during that time I went" picking up a rental car and returning it in Key West actually gave me a much better rental car rate than picking up and returning to Ft Lauderdale. (I didn't return my car in Key West simply because my UA free ticket does not let me fly out of Key West.). When making rental car reservations, you might also ask for a rate on returning rental car on an earlier date, flight schedule permitting. In my case, by returning my rental car one day earlier and taking the cab to my hotel for that one last night (I flew out the following morning), my whole rental car rate went by weekend rate, much lower than the weekday rate - the lower rate affected the whole rental period. That alone saved me about $100.