The genus Harrisia (Cactaceae) comprises 20 species native to South America and the Caribbean. To investigate relationships within the genus, plastid and nuclear markers were sequenced from Harrisia and related genera. Phylogenetic analyses recover a monophyletic Harrisia that can be divided into two subgenera, four sections, and two series. Harrisia likely originated in the Andes and later dispersed into Brazil before further speciation in the Gran Chaco or the Caribbean. A key is given for the taxonomic classifications proposed for Harrisia. New combinations are H. subg. Eriocereus and H. sect. Roseocereus. New taxonomic names are H. sect. Adscendens and H. ser. Earlei.