Well, depends on what you want. Upper Keys, Middle Keys, or Lower.
Upper Keys start at Key Largo (MM 107) and run unofficially down to Tavernier.
Middle Keys start around Islamorada (Upper Matacumbe Key) down through Marathon Key.
Lower Keys finish the islands down to Key West at MM 1.
I'd go with the Middle Keys/Islamorada (Upper and Lower Matacumbe Keys) for a couple of reasons:
1. Good access between the ocean and Florida Bay through Bridges #2 and #5 at the south side of Lower Matacumbe Key. Good fishing there at the bridges if the wind's blowing offshore.
2. Quiet, but resturants and shops close by. You'll find some characters at the bar in the Outback Resturant usually. Chicken dinner at Lazy Days. Go have lunch one day at the 7 Mile Grill in Marathon.
3. Lots of rental properties with docks. You looking for a house with dock or resort?
4. Access to the Isalmorada Humps and Floyd's Wall for offshore fishing.
We used to rent a house on Lower Matacumbe, haven't the last two years though. Went through VRBO without a hitch.
If you go to Key West, lots to do, but obviously more developed and more $$. Fishing can be GREAT going out to the "End of the Bar" and "Cosgrove Shoals" -- both easy runs from Garrision Bight Marina. You'll pay more for lodging there too. You might find a place on Big Coppit Key with a dock -- that'd be best. Since I'm military, I stay at Navy Base when I'm there (if there's room). If you go to Key West, visit Conchy Joe's Tackle, across the street from Garrison Bight Marina on N. Roosevelt Blvd. Rob will take care of you.
PB