<italic>Salvia</italic> subgenus <italic>Calosphace</italic> (<italic>Lamiaceae</italic>), the largest of 5 subgenera with some 500 species and strongly supported as monophyletic, has received no comprehensive systematic research since the initial establishment of 91 taxonomic sections. Representative taxa of 73 sections of <italic>Calosphace</italic> were sampled to investigate the phylogenetic relationships and identify major lineages using chloroplast (intergenic spacer, <italic>psbA-trnH</italic>) and nuclear DNA (ribosomal spacer region, ITS). Phylogenetic analysis of the combined data set established the monophyly of nine sections (<italic>Blakea, Corrugatae, Dusenostachys, Erythrostachys, Hastatae, Incarnatae, Microsphace, Nobiles</italic>, and <italic>Sigmoideae</italic>) and four major lineages (<italic>S. axillaris</italic>, “<italic>Hastatae</italic> clade”, “<italic>Uliginosae</italic> clade”, and “Core <italic>Calosphace</italic>”) corresponding with the four major stamen types identified within the subgenus. Disjunct sections spanning two or more centers of diversity are not supported by the results; no more than seven dispersal events to South America are required to account for the current disjunct distributions. One member of the subgenus, <italic>Salvia divinorum</italic> is hallucinogenic and used in traditional healing ceremonies by the Mazatec of Mexico. It was classified within section <italic>Dusenostachys</italic> and hypothesized to be an interspecific hybrid. Multiple DNA regions (ITS, <italic>trnL-trnF</italic>, and <italic>psbA-trnH</italic>) of 52 species representing the major lineages of subgenus <italic>Calosphace</italic> and six accessions of <italic>S. divinorum</italic> were sequenced to test its phylogenetic position and putative hybridity. <italic>Salvia divinorum</italic> should not be classified within <italic>Dusenostachys</italic> nor is it a hybrid according to the results; its closest relative is <italic>S. venulosa</italic>, a Colombian endemic. In addition to <italic>S. divinorum</italic>, there are many other <italic>Calosphace</italic> species that are used medicinally in North and South America. Ethnobotanical data was gathered for 150 species; those sharing the common names, medicinal uses, appearances, and similar compounds associated into medicinal plant complexes. Five new, previously undocumented complexes were identified: <italic>Mirto</italic> (5 spp. used extensively in the treatment of <italic>susto</italic> and other illnesses in Mexico), <italic>Ñucchu</italic> (7 spp. used as a symbolic element in religious prossessions and in the treatment of respiratory ailments in Peru), <italic>Lí'l++</italic> (3 spp. used for food and medicine by the Chianantec), <italic>Cantueso</italic> (2 spp. used for respiratory ailments in Mexico), and <italic>Manga-paqui</italic> (3 spp. used for kidney and liver problems in Ecuador).