A comprehensive taxonomic revision of the genus Pachycereus (Cactaceae, Cactoideae, Pachycereeae) is presented. Pachycereus is characterized by one synapomorphic character, the presence of a narrow interareolar groove, and by the combination of flowering region differentiated with flexible spines, flower with a narrow region between the pericarpel and the receptacular tube and the occurrence of trichomes and short spines in the pericarpel. Five species are recognized in the present treatment. One species (P. pecten-aboriginum) is widely distributed from Chihuahua in northern Mexico to Chiapas, three species (P. grandis, P. pringlei, and P. weberi) are restricted to defined floristic provinces, and one species (P. tepamo) is endemic to Depresion del Balsas. A key and descriptions of the species, based on herbarium specimens, field observations and intensive field collection are presented. The taxonomic history, synonymies, distribution, uses, and representative specimens are included. Three new combinations, Pterocereus gaumeri subsp. foetidus, Lemaireocereus lepidanthus, and Lophocereus marginatus, are proposed.