Cayratia consists of ca. 60 species primarily distributed in the tropical and subtropical regions of Asia, Australia, and Africa. It is an excellent candidate for exploring the evolution of intercontinental disjunct distributions in the Old World. Previous phylogenetic work of Vitaceae with a few species of Cayratia sampled showed that Cayratia was not monophyletic and was closely related to Cyphostemma and Tetrastigma. We herein expanded taxon sampling of Cayratia (25/60 species) with its allied genera Cyphostemma (39/150 species), Tetrastigma (27/95 species), and other related genera from Vitaceae represented, employing five plastid markers (atpB-rbcL, rps16, trnC-petN, trnH-psbA, and trnL-F), to investigate the phylogeny, character evolution and biogeography of Cayratia. The phylogenetic analyses have confirmed the monophyly of the Cayratia-Cyphostemma-Tetrastigma (CCT) clade and resolved Cayratia into three lineages: the African Cayratia clade, subg. Cayratia, and subg. Discypharia. The African Cayratia was supported as the first diverging lineage within the CCT clade and Tetrastigma is resolved as sister to subg. Discypharia. Character optimizations suggest that the presence/absence of a membrane enclosing the ventral infolds in seeds is an important character for the taxonomy of Cayratia. The presence of bracts on the lower part of the inflorescence axis is inferred to have arisen only once in Cayratia, but this character evolved several times in Tetrastigma. Both the branching pattern of tendrils and the leaf architecture are suggested as important infrageneric characters, but should be used cautiously because some states evolved multiple times. Ancestral area reconstruction and molecular dating suggest that the CCT clade originated from continental Africa in the late Cretaceous, and it then reached Asia twice independently in the late Cretaceous and late Oligocene, respectively. Several dispersals are inferred from Asia to Australia since the Eocene.