Understanding the patterns, causes, and consequences of biotic interchange—the movement of species between neighboring biotas—is crucial for evaluating the effects of human-introduced species in the modern biosphere. Since at least the early Miocene, the tropical and subtropical western Atlantic has comprised two biogeographic provinces, the Gatunian (including the Caribbean) and the Caloosahatchian (North Carolina to Florida and the Yucatán peninsula). Although these adjacent provinces are not separated by a land barrier, exchange of species between them has been limited and intermittent. A synthesis of taxonomic, phylogenetic, stratigraphic, and biogeographic data on six gastropod and two bivalve groups reveals a dramatic shift in the pattern of interchange between these provinces. About 31% of early Miocene Caloosahatchian subgenus- and species-group-level taxa invaded the Gatunian Province by the late Miocene, but no taxa extended their ranges in the opposite direction. Beginning in the early Pliocene and continuing into the early Pleistocene, 40 taxa (roughly one-third of Gatunian diversity) invaded the Caloosahatchian Province from the Caribbean, whereas only four taxa extended their range from Florida into the Caribbean.Comparisons between the ranked percentage of Gatunian invaders in Florida and the magnitude of regional extinction there for each of four middle Pliocene to early Pleistocene intervals reveal no consistent relation between invasion and prior or concurrent extinction. During the Pliocene, invaders not only compensated for extinctions, but also accounted for almost all the observed increase in standing diversity in Florida. Only after the large extinction event at the end of the Pliocene did invaders from the Gatunian Province not fully compensate for the loss of species.Although the Miocene interaction between the Gatunian and Caloosahatchian biotas involved two fully tropical entities, the Plio–Pleistocene interaction exemplifies a general pattern in which tropical species often spread to higher latitudes during warm intervals, but warm-temperate or subtropical species rarely become established in the Tropics. Some evidence indicates that tropical Caribbean molluscs are exposed and adapted to more intense competition and predation than their subtropical counterparts in Florida, implying a role for individual-level biotic interactions in determining the predominant direction of interchange. Intensification of north-flowing currents in the western Atlantic may also contribute to the nearly one-way movement of taxa from the Caribbean to Florida during the Pliocene and early Pleistocene. The changing pattern of interchange from the Miocene to the Pliocene further reflects a change in the geography of species richness, with the richer province serving as the chief donor and the province with lower diversity acting as the main recipient of invaders. Diversity, ocean circulation, and the competitive environment thus account for the observed switch in the predominant direction of invasion in the western Atlantic during the Neogene.The fact that almost 90% of Gatunian immigrants to Florida differentiated taxonomically there indicates that invasion is intermittent. Long-term consequences of this and many other cases of interchange between provinces include enrichment of the regional and global species pool and the spread of adaptations reflecting intense competition and predation.