We used distribution data of 121 cactus species endemic to the Chihuahuan Desert to test the effectiveness of the region’s protected area network. The analysis of species distribution using a 30′ latitude × 30′ longitude grid facilitated the identification and categorization of areas of endemism. We found a low degree of coincidence between protected areas and the areas of cactus endemism, and only 63.6% of the 121 species occur in protected areas. A complementarity analysis showed that 10 of the protected areas contain the 77 species that occur in protected areas. The four top priority areas protect 65 (84.4%) of these 77 species The 44 unprotected species are mainly micro-endemic and taxonomically distinctive taxa widely scattered in the region. The complementarity analysis applied to these species showed that all of them can be contained in a minimum of 24 grid squares, representing 32.9% of the total area occupied. Their strong spatial dispersion, along with their narrow endemism, is a major conservation challenge. We conclude that the current protected area network is insufficient to protect the rich assemblage of cacti endemic to the Chihuahuan Desert. Conservation efforts in this region should be enhanced by increasing the effectiveness of the already existing protected areas and by the creation of additional protected areas, specifically micro-reserves, to provide refuge for the unprotected species.