Cynanchum constitutes one of the very few Asclepiadoid genera that are distributed both in the Old and the New World. The present study of more than 100 species, based on Bayesian and maximum likelihood analysis of five chloroplast and four nuclear markers, resolves nine clades. No unambiguous morphological characters are associated with any particular clade or a combination of several clades, so that a wide concept of Cynanchum seems the most appropriate taxonomic solution for the group. For this reason, several hitherto independent genera, Glossonema, Graphistemma, Holostemma, Metalepis, Metaplexis, Odontanthera, Pentarrhinum, Raphistemma and Seshagiria are included in Cynanchum. In addition, Adelostemma and Sichuania are subsumed under Cynanchum for morphological reasons. The necessary new combinations are made, resulting in twelve new species combinations, two new subspecies combinations, and two new names.