We use data from the internal transcribed spacer (ITS) region of the nuclear rDNA cistron and the chloroplast psbA–trnH intergenic spacer to reconstruct the phylogenetic relationships among southern African species of Euphorbia. The results indicate that major re–organization is necessary of the groupings within Euphorbia that have been recognised in the past, since most of them turn out to be polyphyletic. Furthermore, in its present circumscription, Euphorbia itself is not monophyletic, nor do the southern African species form a monophyletic group. Both datasets show that the southern African species fall into four major groups, which we recognise as subgenera: Chamaesyce Raf., Esula Pers., Euphorbia and Rhizanthium (Boiss.) Wheeler. To accommodate the southern African species, subg. Chamaesyce is divided into sect. Chamaesyce, sect. Frondosae Bruyns, sect. nov., sect. Articulofruticosae Bruyns, sect. nov. and sect. Espinosae Pax & Hoffm. Subgenus Euphorbia is divided into sect. Euphorbia, sect. Monadenium (Pax) Bruyns, sect. Goniostema H. Baill. ex Boiss. and sect. Tirucalli Boiss. To re–establish the monophyly of Euphorbia, the genera Endadenium L. C. Leach, Monadenium Pax and Synadenium Boiss. are reduced to synonymy under Euphorbia subg. Euphorbia sect. Monadenium and the species are all transferred to Euphorbia. Consequently the subtribe Euphorbiinae now consists of the single, very large, very widely distributed and very diverse genus Euphorbia. Three of the subgenera (Chamaesyce, Esula, Euphorbia) are nearly cosmopolitan, showing the great age and wide extent of the radiation that has occurred within Euphorbia. The remaining subg. Rhizanthium is mainly African.