This investigation establishes the first sequence-based phylogenetic hypothesis of species relationships in the Coca family (Erythroxylaceae). We focused our phylogenomic inference on the largest taxonomic section in the genus Erythroxylum (Archerythroxylum O. E. Schulz) using concatenation and gene tree reconciliation methods from hybridization-based target capture of 427 genes. We show that Neotropical Erythroxylum are monophyletic within the Paleotropical lineages, yet Archerythroxylum and all of the other taxonomic sections from which we sampled multiple species lack monophyly. We mapped phytogeographic states onto the tree and found some concordance between these regions and clades. The wild species E. gracilipes and E. cataractarum are most closely related to the cultivated E. coca and E. novogranatense but relationships within this “coca” clade remain equivocal, suggesting a more complicated origin than Plowman’s single-domestication hypothesis. Our results point to the difficulty of morphology-based intrageneric classification in this clade and highlight the importance of integrative taxonomy in future systematic revisions. In compliance with data protection regulations, please contact the publication office if you would like to have your personal information removed from the database.