Molecular phylogenetic studies of the six currently accepted species in the genus Echinocactus have partially clarified certain aspects of its phylogeny. Most of the studies lack a complete sampling of Echinocactus and are based only in one source of data. Phylogenetic uncertainties in Echinocactus, such as the recognition of Homalocephala as a different genus from Echinocactus, the exclusion of E.grusonii or the affinities of E.polycephalus, are here resolved. Phylogenetic relationships of Echinocactus were reconstructed with a maximum parsimony, a maximum likelihood and a Bayesian approach including 42 morphological characters, four chloroplast markers (atpB-rbcL, trnH-psbA, trnL-trnF and trnK/matK) and two nuclear genes. The utility of these two nuclear regions related to the betalain cycles (DODA and 5GT) are explored and discussed in relation to their potential as phylogenetic markers. Concatenated analyses with morphological and molecular data sets, plus 13 indels (2847 characters and 26 taxa), show general agreement with previous independent phylogenetic proposals but with strong support in order to propose the recognition of a reduced Echinocactus and the recognition of Homalocephala at the generic level. These results recovered a polyphyletic Echinocactus as currently defined. The here-named HEA clade, recovers the species of Homalocephala, Echinocacuts and Astrophytum as a monophyletic group with strong internal support. The Homalocephala (H.texensis, H.parryi and H.polycephala), was recovered as sister to the Echinocactus clade (E.platyacanthus and E.horizonthalonius), plus the Astrophytum clade. Consequently, we propose here to recognise a monophyletic Echinocactus and a monophyletic Homalocephala as two distinct genera with their own molecular and morphological synapomorphies. The evolution of some morphological characters supporting these clades are discussed, the necessary new taxonomic combinations for Homalocephala are proposed and an identification key for the genera, the species and the subspecies of the HEA clade are presented.