The Caribbean land mammal fauna was formerly species-rich and diverse, but has experienced extensive postglacial extinctions that have been staggered through time and have varied in intensity between different islands. The Caribbean therefore has the potential to represent an extremely informative study system to understand wide-scale macroecological patterns of mammalian vulnerability and resilience, and provide important insights into global extinction dynamics. However, the spatiotemporal pattern of Caribbean mammal survival and extinction is complex, and research into correlates of extinction risk for this fauna has so far been limited and largely qualitative. We present the results of a new macroecological analysis investigating both intrinsic (biological, evolutionary) and extrinsic (environmental, anthropogenic) correlates of extinction vulnerability and resilience across the endemic Holocene land mammal fauna of the Caribbean (including rodents, sloths, primates and lipotyphlans) within a rigorous statistical and phylogenetically explicit framework, and present a new evidence-base for assessing why some Caribbean species and islands have been more prone to experience extinction through time. Extinction risk data from this analysis of historical baselines are interpreted within the context of the status and ecology of surviving Caribbean mammals, to evaluate the extent to which the past can be used to inform conservation in the present. The “last survivors” of the Caribbean land mammal fauna may now be threatened by multiple factors, and we complement our fauna-wide macroecological analysis with further analysis of remote-sensing data, to evaluate whether primary extinction drivers can be identified for some of Cuba’s most threatened mammal species.