Subgenus Grammica, the largest and most diverse group in the parasitic genus Cuscuta, includes 130 species distributed primarily throughout the New World, with Mexico as its center of diversity. To circumscribe the subgenus and assess the relationships among its major lineages, we conducted the first phylogenetic study of Grammica using plastid trnL-F and nrITS sequences from a wide taxonomic sampling covering its morphological, physiological, and geographical diversity. With the exception of one species belonging elsewhere, the subgenus was found to be monophyletic. The results further indicate the presence of 15 well-supported major clades within Grammica. Some of those lineages correspond partially to earlier taxonomic treatments, but the majority of groups are identified in this study for the first time. The backbone relationships among major clades, however, remain weakly supported or unresolved in some cases. The phylogenetic results indicate that the fruit dehiscence character is homoplastic, thus compromising its value as a major taxonomic and evolutionary feature. While several striking cases of long-distance dispersal are inferred, vicariance emerges as the most dominant biogeographical pattern for Cuscuta. Species placed within one of the clades with a predominantly South American distribution are hypothesized to have substantially altered plastid genomes.