Macaranga and Mallotus (Euphorbiaceae s.s.) are two closely related, large paleo(sub)tropical genera. To investigate the phylogenetic relationships between and within them and to determine the position of related genera belonging to the subtribe Rottlerinae, we sequenced one plastid (trnL-F) and three nuclear (ITS, ncpGS, phyC) markers for species representative of these genera. The analyses demonstrated the monophyly of Macaranga and the paraphyly of Mallotus and revealed three highly supported main clades. The genera Cordemoya and Deuteromallotus and the Mallotus sections Hancea and Oliganthae form a basal Cordemoya s.l. clade. The two other clades, the Macaranga clade and the Mallotus s.s. clade (the latter with Coccoceras, Neotrewia, Octospermum, and Trewia), are sister groups. In the Macaranga clade, two basal lineages (comprising mostly sect. Pseudorottlera) and a crown group with three geographically homogenous main clades were identified. The phylogeny of the Mallotus s.s. clade is less clear because of internal conflict in all four data sets. Many of the sections and informal infrageneric groups of Macaranga and Mallotus do not appear to be monophyletic. In both the Macaranga and Mallotus s.s. clades, the African and/or Madagascan taxa are nested in Asian clades, suggesting migrations or dispersals from Asia to Africa and Madagascar.