Premise of the study: The Chamaesyce clade of Euphorbia is the largest lineage of C 4 plants among the eudicots, with 350 species including both narrow endemics and cosmopolitan weeds. We sampled this group worldwide to address questions about subclade relationships, the origin of C-4 photosynthesis, the evolution of weeds, and the role of hybridization and long-distance dispersal in the diversification of the group. Methods: Two nuclear (ITS and exon 9 of EMB2765) and three chloroplast markers (matK, rpl16, and trnL-F) were sequenced for 138 ingroup and six outgroup species. Exon 9 of EMB2765 was cloned in accessions with >1% superimposed peaks. Key results: The Chamaesyce clade is monophyletic and consists of three major subclades [1(2,3)]: (1) the Acuta clade, containing three North American species with C 3 photosynthesis and C-3-C-4 intermediates; (2) the Peplis clade, mostly North American and entirely C-4; and (3) the Hypericifolia clade, all C-4, with both New World and Old World groups. Incongruence between chloroplast and ITS phylogenies and divergent cloned copies of EMB2765 exon 9 suggest extensive hybridization, especially in the Hawaiian Islands radiation. Conclusions: The Chamaesyce clade originated in warm, arid areas of North America, where it evolved C-4 photosynthesis. From there, it diversified globally with extensive reticulate evolution and frequent long-distance dispersals. Although many species are weedy, there are numerous local adaptations to specific substrates and regional or island radiations, which have contributed to the great diversity of this group.