Phylogenetic relationships within tribe Phyllantheae, the largest tribe of the family Phyllanthaceae, were examined with special emphasis on the large genus Phyllanthus. Nuclear ribosomal ITS and plastid matK DNA sequence data for 95 species of tribe Phyllantheae, including representatives of all subgenera of Phyllanthus (except Cyclanthera) and several hitherto unplaced infrageneric groups, were analyzed. Results for ITS and matK are generally concordant, although some species are placed differently in the plastid and ITS trees, indicating that hybridization/paralogy is involved. Results confirm paraphyly of Phyllanthus in its traditional circumscription with embedded Breynia, Glochidion, Reverchonia, and Sauropus. We favor the inclusion of the embedded taxa in Phyllanthus over further generic segregation. Monophyletic Phyllanthus comprises an estimated 1269 species, making it one of the "giant" genera. Phyllanthus maderaspatensis is sister to all other species of Phyllanthus, and the genus appears to be of paleotropical origin. Subgenera Isocladus, Kirganelia, and Phyllanthus are polyphyletic, whereas other subgenera appear to be monophyletic. Monotypic Reverchonia is sister to P. abnormis, arborescent section Emblica to herbaceous Urinaria, free-floating aquatic P. fluitans to the weed P. caroliniensis, and the phyllocladous section Choretropsis to the delicate leafy P. claussenii. The unique branching architecture known as "phyllanthoid branching" found in most Phyllanthus taxa has been lost (and/or has been derived) repeatedly. Taxonomic divisions within Phyllantheae based on similar pollen morphology are confirmed, and related taxa share similar distributions. We recommend recognition of six clades at generic level: Flueggea s.l. (including Richeriella), Lingelsheimia, Margaritaria, Phyllanthus s.l. (including Breynia, Glochidion, Reverchonia, and Sauropus), P. diandrus, and Savia section Heterosavia.