We analysed phylogenetic relationships in the order Cucurbitales using 14 DNA regions from the three plant genomes: the mitochondrial nadl b/c intron and matR gene, the nuclear ribosomal 18S, ITS1-5.8S-ITS2, and 28S genes, and the plastid rbcL, matK, ndhF, atpB, trnL, trnL-trnF, rpl20-rps12, trnS-trnG and trnH-psbA genes, spacers, and introns. The dataset includes 664 ingroup species, representating all but two genera and over 25% of the ca. 2600 species in the order. Maximum likelihood analyses yielded mostly congruent topologies for the datasets from the three genomes. Relationships among the eight families of Cucurbitales were: (Apodanthaceae, Anisophylleaceae, (Cucurbitaceae, ((Coriariaceae, Corynocarpaceae), (Tetramelaceae, (Datiscaceae, Begoniaceae))). Based on these molecular data and morphological data from the literature, we recircumscribe tribes and genera within Cucurbitaceae and present a more natural classification for this family. Our new system comprises 95 genera in 15 tribes, five of them new: Actinostemmateae, Indofevilleeae, Thladiantheae, Momordiceae, and Siraitieae. Formal naming requires 44 new combinations and two new names in Cucurbitaceae.