The West Indian mammal fauna has played a key role in the development of biogeographic ideas for over a century, but a synthesis explaining regional patterns of mammal diversity and distribution in a historical framework has not emerged. We review recent phylogenetic, population genetic, and radiocarbon dating studies of West Indian mammals and explore the biological and historical drivers of colonization, speciation, and extinction in this region of endemism. We also present the i rst complete list of all its extant and extinct mammals. The mammalian biota is older than was earlier presumed, with many ancient endemic lineages, even among highly vagile organisms such as bats. Land bridges, Cenozoic eustatic sea-level changes, and Pleistocene glacial cycles have been proposed to explain the colonization of the islands, but phylogenetic divergence analyses often conflict with the timing of these events and favor alternative biogeographic histories. The loss of West Indian biodiversity is incompletely understood, but new radiometric chronologies indicate that anthropogenic impacts rather than glacial-interglacial environmental changes are responsible for most Quaternary extinction and extirpation events involving land mammals. However, many outstanding questions of historical biogeography remain unresolved, including appropriate methods for interpreting phylogenies and divergence estimates in a biogeographic context, and whether to use vicariance or dispersal as the null hypothesis when investigating regional patterns of colonization, speciation, and extinction in comparative analyses. We propose synthetic approaches drawing from phylogenetics, population genetics, paleogeography, paleontology, and even archaeology to resolve persisting questions in Caribbean biogeography.