Salvia subgenus Calosphace (Lamiaceae) is economically and ethnomedicinally significant and comprised of more than 500 species. Although strongly supported as monophyletic, it has received no comprehensive systematic research since the initial establishment of 91 taxonomic sections in 1939. Representative taxa of 73 sections of Calosphace were sampled to investigate the phylogenetic relationships and identify major lineages using chloroplast (intergenic spacer psbA-trnH) and nuclear ribosomal DNA (internal transcribed spacer). Phylogenetic analysis of the combined data sets established monophyly of seven sections (Blakea, Corrugatae, Erythrostachys, Hastatae, Incarnatae, Microsphace, and Sigmoideae) and four major lineages (S. axillaris, “Hastatae clade”, “Uliginosae clade”, and “core Calosphace”). Sections spanning two or more centers of diversity are not supported by our results; rather, supported relationships exhibit significant geographic structure. Mexico is supported as the geographic origin of Calosphace, and no more than seven dispersal events to South America are required to account for current disjunct distributions.