Understanding the origin of island endemics is a central task of historical biogeography. Recent methodological advances provide a rigorous framework to determine the relative contribution of different biogeographic processes (e.g., vicariance, land migration, long-distance dispersal) to the origin of island endemics. With its complex but well-known history of microplate movements and climatic oscillations, the Mediterranean region (including the Mediterranean basin and Macaronesia) provides the geographic backdrop for the diversification of Ruta L., the type genus of Rutaceae (citrus family). Phylogenetic, molecular dating, and ancestral range reconstruction analyses were carried out to investigate the extent to which past geological connections and climatic history of the Mediterranean region explain the current distribution of species in Ruta, with emphasis on its island endemics. The analyses showed that Ruta invaded the region from the north well before the onset of the Mediterranean climate and diversified in situ as the climate became Mediterranean. The continental fragment island endemics of the genus originated via processes of land migration/vicariance driven by connections/disconnections between microplates, whereas the oceanic island endemics were the product of a single colonization event from the mainland followed by in situ diversification. This study emphasizes the need for an integrative, hypothesis-based approach to historical biogeography and stresses the importance of temporary land connections and colonization opportunity in the biotic assembly of continental fragment and oceanic islands, respectively.