Mapping biodiversity patterns across taxa and environments is crucial to address the evolutionary and ecological dimensions of species distribution, suggesting areas of particular importance for conservation purposes. Within Cactaceae, spatial diversity patterns are poorly explored, as well as the abiotic factors that may predict these patterns. We gathered geographic and genetic data from 922 cactus species, which are tightly associated with drylands, to evaluate diversity patterns, such as phylogenetic diversity and endemism, paleo-, neo-, and superendemism, and the environmental predictor variables of such patterns in a global analysis. Hotspot areas of cacti diversity are scattered along the Neotropical and Nearctic regions, mainly in the desertic portion of Mesoamerica, Caribbean Island, and the dry diagonal of South America. The geomorphological features of these regions may create a complexity of areas that work as locally buffered zones over time, which triggers local events of diversification and speciation. Desert and dryland/dry forest areas comprise paleo- and superendemism and may act as both museums and cradles of species, displaying great importance for conservation. Past climates, topography, soil features, and solar irradiance seem to be the main predictors of distinct endemism types. The hotspot areas that encompass a major part of the endemism cells are outside or poorly covered by formal protection units. The current legally protected areas are not able to conserve cactus evolutionary history. Given the rapid anthropogenic disturbance, efforts must be reinforced to monitor biodiversity and the environment and to define/plan current and new protected areas.