This paper summarizes the taxonomic findings of the three cruises on board of Florida Institute of Oceanography research vessels Bellows and Suncoaster conducted between 2000 and 2005 as well as to discuss the unique regional oceanographic settings that were found to be essential in supporting the diverse and unique bathyal molluscan fauna encountered in the depths of the eastern Straits of Florida. Approximately 30 stations were sampled, from South Cat Cay (25°42.085′N) through Victory Cay (25°28.355′N), at depths ranging from 120–600 meters and averaging 400 m depth. A total of 74 molluscan taxa belonging to 34 families were identified from over 400 individual mollusk specimens. The gastropods Architectonica sunderlandi Petuch 1987, Bursa finlayi McGinty 1962, and Exilia meekiana (Dall, 1889a) were collected from the eastern side of the Straits of Florida for the first time. The Ranellid Pisanianura grimaldii (Dautzenberg, 1889) is reported from the western Atlantic Ocean for the first time. Two new taxa are described, including a new species of eratoid, Hespererato pallida, new species, and a new species of volute, Scaphella (Scaphella) biminiensis, new species. Additionally, a number of rare or otherwise poorly known molluscan taxa are illustrated, described, and discussed in context of the oceanographic settings from which they were collected. The presence of a diverse and unique deep-water molluscan community is attributed to the distinctive current structure and temperature asymmetry that has been observed between the western and eastern slopes of the Straits of Florida.