If you're arriving by car then the easiest to reach will be Key Largo which is the first major town as you come down the 1. This is a very busy area by Keys standards, but again it does have the virtue of being closest to the mainland and MIA, and I don't know the set-up with game fishing operators but I'm sure it has one or more reputable ones. For a quieter getaway you should consider Islamorada, which has plenty of dining choices and one of the best big game fishing operators in the Keys, called Bud N' Mary's. Check their website at: www.budnmarys.com, toll-free tel: 1-800 742-7945. They've been in operation for over 40 years and have hosted many well-known figures over the years. They also have rooms to rent. I personally stayed at Cheeca Lodge up the road but this hotel has recently had a huge fire in the past 10 days that damaged much of the main building and dining area.