AbstractCleomaceae is a small pantropical family that is emerging as a promising system to investigate C4 photosynthesis, floral evolution, and comparative genomics. However, our understanding of these phenomena is hindered by a lack of a strong phylogenetic hypothesis, despite a number of previous studies. We reconstructed the phylogeny of the family using data from all three genomes, including three cpDNA (ndhF, matK, ycf1), one mtDNA (rps3), and one nrDNA (ITS) regions. Analyses strongly supported 15 clades: (1) Clade 1, which includes two Old World species, Cleome khorassanica and C. turkmena; (2) Cleome s.str., which includes the type C. ornithopodioides and Old World species; (3) Droserifolia, corresponding to three Old World species, C. droserifolia, C. fimbriata, C. quinquenervia; (4) Polanisia, equivalent to this New World genus; (5) Angustifolia, which includes four Old World species; (6) North American cleomoids, which includes four genera, Cleomella, Peritoma, Oxystylis, and Wislizenia; (7) Australian, which includes Old world species and worldwide weed Arivela viscosa; (8) Gynandropsis, equivalent to this monotypic genus; (9) Clade 6, which includes Old World species of Cleome and Dipterygium; (10) Dactylaena, corresponding to this genus and Physostemon; (11) African, which includes species distributed in Old World; (12) Andean, which includes Podandrogyne and tropical New World species of Cleome; (13) Melidiscus, which includes New World tropical species; (14) Cleoserrata, which includes New World tropical species; and (15) Tarenaya, a large New World clade. Major relationships amongst the clades are strongly supported for the first time, including North American cleomoids sister to all remaining Cleomaceae. While five genera are confirmed or newly identified here to be non‐monophyletic (Cleome, Cleomella, Hemiscola, Peritoma, Tarenaya), six are supported (Cleoserrata, Dactylaena, Melidiscus, Physostemon, Podandrogyne, Polanisia). Thus, there are many taxonomic and evolutionary implications to our revised phylogenetic hypothesis.