The ten countries that make up southern Africa are collectively a hot-spot of medicinal plant knowledge, with a unique preference for the utilization of bark over leaves from possibly hundreds of species. The most popular 86 medicinal bark species were identified in an earlier survey of various muthi markets around Johannesburg, and are listed in the current review, out of which chemical data was found for 63 and tabulated. The chemistry of medicinal bark species is, however, incomplete, since many scholars focused their research on metabolites of interest to their research groups, such as essential oils, lipophilic compounds, alkaloids or saponins, to the exclusion of other specialized metabolites present in the respective biota. From the current phytochemical analysis, the medicinal potential of bark relative to leaves is not obvious, as it is dependent on factors such as quantity of specialized metabolites (potency), their identities and anecdotal accounts from traditional healers. Nevertheless, the preference for bark may be due to empirical outcomes in therapy. Southern African medicinal bark species demonstrate an extremely diverse pool of unique/new or relatively unheard of natural products, such as calondendrolide from C. capense, combretastatin from C. caffrum, capensin from C. capense, crotohalimaneic acid from C. sylvaticus, ekebergins from E. capensis, entandrophragmin from E. caudatum, lysisteisoflavone from E. lysistemon, kigelinone from K. africana, holstinones from O. holstii, piptadeniaoside from P. africanum, rauvolfianoids from R. caffra, tetrapterosides from T. tetraptera, voacangine from V. thouarsii, warburganal from W. salutaris and mucronine from Z. mucronata. The review concludes by briefly commenting on pharmacokinetic aspects associated with ingestion or topical application of bark metabolites.