Background: Knowledge of endemism in a region (natural or political) is fundamental to determining natural biogeographic regions and establishing conservation priorities. Questions: How many vascular plant species are endemic to the state of Puebla? What is the geographic distribution of endemism in the state? Are there centers of phylogenetic endemism? Studied species: 356 species of vascular plants. Study site: State of Puebla, Mexico. Methods: Based on the literature review and botanical specimens in digitized databases, the vascular plant species endemic or nearly endemic to the state of Puebla, Mexico, was assessed. Using a grid cell 1° × 1° latitude and longitude size, the incidence of each species was assessed. With the above information and a phylogeny of the species, a spatial phylogenetic analysis was carried out to detect centers of phylogenetic endemism. Results: 82.6 % of the 356 endemic species to Puebla are distributed in only one to three grid cells. The spatial phylogenetic analysis revealed centers of high phylogenetic diversity and endemism as well as delineated centers of mixed and paleo-endemism. Conclusions: The state of Puebla contains areas that meet the criteria to be considered centers of species endemism. Strategies toward a better understanding of plant endemism, as here proposed, suggest a better comprehension of the chorology of Mexican endemism, and assess the true role of our natural protected areas in conserving endemic species.