Acalypha (Euphorbiaceae Acalyphoideae) is a large, monophyletic genus distributed worldwide in tropical and subtropical regions, with a few species extending into temperate Asia and North America. We reconstructed phylogenetic relationships within the genus using DNA sequences from the plastid ndhF and trnL-F regions and the nuclear ribosomal ITS region, sampling 143 species to represent the geographic, morphologic, and taxonomic diversity with the genus, resulting in a 162 (158 in Acalypha) terminal and 3847 character combined dataset. Bayesian and maximum likelihood reconstructions based on the combined dataset yielded a tree with a generally well-supported backbone and several strongly supported clades. Our results strongly supported the monophyly of subg. Acalypha as currently recognized but showed that subg. Linostachys and almost all other infrageneric taxa recognized in the most recent comprehensive classification of the genus were not monophyletic. We therefore propose a new subgeneric classification comprising subg. Acalypha, subg. Androcephala, subg. Hypandrae, and subg. Linostachys (s.s.). Our results also shed light on relationships within some species groups, including in what has been treated as a broadly defined A. amentacea, in which we recognize A. amentacea, A. palauensis comb. nov., and A. wilkesiana as distinct species. Bayesian ancestral state estimations based on the phylogeny of Acalypha demonstrated that plant habit and inflorescence position and sexuality are highly homoplastic, especially within subg. Acalypha, and that inflorescence position and habit exhibit correlated evolution.