Madagascar’s huge size and long history of isolation have assured ongoing debate about both the origin of its oddly constituted fauna and the nature of the major extinction event that occurred following the first incursion of humans onto the island some two thousand years ago. In this paper I briefly review the geological and biological evidence for the origin of the modern Malagasy fauna, and examine the potential roles of direct human intervention and climatic change in the extinction of Madagascar’s large-bodied mammals. Despite the remarkable dearth of evidence for direct interaction between humans and the island’s ‘subfossil’ fauna, available evidence of climatic conditions in Madagascar since the end of the Pleistocene does not indicate that its fauna was under unprecedented environmental stress in this period. It is thus impossible to avoid the conclusion that human activity played a critical role in the elimination of several dozen species of mammals and birds of larger body size than their surviving relatives. In turn, this observation underscores the fact that the documented extinctions do not constitute a static and completed historical phenomenon, but rather form part of an ongoing process that continues today to menace Madagascar’s unique fauna and flora.