Euphorbia subg. Euphorbia is the largest and most diverse of four recently recognized subgenera within Euphorbia and is distributed across the tropics and subtropics. Relationships within this group have been difficult to discern due mainly to homoplasious morphological characters and inadequate taxon sampling in previous phylogenetic studies. Here we present a phylogenetic analysis of E. subg. Euphorbia, using one nuclear and two plastid regions, for the most complete sampling of molecular sequence data to date. We assign 661 species to the subgenus and show that it is comprised of four highly supported clades, including a single New World clade and multiple independent lineages on Madagascar. Using this phylogenetic framework we discuss patterns of homoplasy in morphological evolution and general patterns of biogeography. Finally, we present a new sectional classification of E. subg. Euphorbia comprising 21 sections, nine of them newly described here.