The Florida Keys extend nearly 320 km (200 miles) in a southwesterly direction south of the Florida Mainland. They are unique in their geology and ecology and, given their isolation, they harbor many rare taxa and ecological complexes. The Keys reef tract is the largest in North America, as are the tracts of mangroves fringing the mainland and forming countless islets in Florida Bay and the Gulf of Mexico. The Keys also harbor archaeological sites dating back several millennia and are important economically given the estimated five million visitors per year. Both terrestrial and aquatic habitats in and around the Keys, and the many species they support, are fragile and under a great many threats ranging from exotic species to poor water quality, diseases, boat and motor traffic, and sea level rise. Here I explore the workings of the county, state, and federal agencies that maintain the vast system of both aquatic and terrestrial protected areas throughout the Florida Keys and adjacent areas on the mainland and consider their roles in regional conservation. I finish with thoughts on the potential for broad-scale conservation coordination efforts in this fascinating part of the country.