Milkweeds (Asclepias s. l., Apocynaceae) are characteristic perennial herbs of grasslands in North America and Africa that have long served as models for studying the evolutionary ecology of plant reproduction and plant defense. Generic circumscription of Asclepias has been long debated with recent workers favoring delimitation on geographic grounds; Asclepias s. s. is limited to the Americas and only segregate genera are recognized for African species. A widely used system introduced by Woodson classifies North American Asclepias into nine subgenera, with the largest subgenus, Asclepias, further divided into eight series. We investigated the phylogeny of Asclepias using three noncoding loci from the plastid genome: rpl16 intron, trnC^GCA—rpoB spacer, and the adjacent trnS^GCU—trnG^uuc spacer and trnG^uuc intron. Parsimony, likelihood, and Bayesian analyses were conducted to evaluate hypotheses of continental and taxonomic monophyly. Hypothesis tests were conducted under the parsimony and likelihood criteria. We found moderate support for the monophyly of American Asclepias s. s. and for all but one representative of African Asclepias s. l. Within the Amerian clade, South American species are strongly supported as monophyletic and derived from North American ancestors. Only one of Woodson's 17 infrageneric taxa was found to be monophyletic. Monophyly of more than one half of the remaining 16 taxa could be statistically rejected using a conservative α level. Our results are consistent with taxonomic restriction of Asclepias to American species and single colonization events from Africa to North America and North America to South America. They also point to a need for major restructuring of infrageneric classification and future revsionary work.