Numerous 'scaffolds' that have been identified in natural product structures have led to very significant numbers of approved drugs and drug candidates for a multiplicity of diseases over the years. In this mini-review, we discuss the base scaffolds (chemical skeletons) that we feel have produced very significant numbers of agents as drugs or drug leads and, in a number of cases, compounds that can be used as chemical synthons or that present activities in biological areas that were not obvious from their earlier history.