The landscape of small-molecule drug discovery has undergone substantial changes over the past 20 years, in which the testing of tens to hundreds of compounds in animal models was replaced by the high-throughput screening (HTS) of megalibraries against modified cell lines or isolated biomolecular targets. Natural products were a fruitful source of lead molecules, but their impact waned considerably since their heyday between the 1940s and 1960s. During the 1990s, pharmaceutical companies began to invest heavily in the HTS of combinatorial chemistry libraries that typically contained compounds with non-natural (synthetic) motifs. Incredibly, the contribution by natural products towards lead molecules (chemical starting points) and drugs remained steady despite the diversion of resources and the general decline in discovery. An analysis covering the 30-year period to December 2010 indicated that approximately 39% of all 1,068 small-molecule new chemical entities were either a natural compound, close semi-synthetic analogue or a synthetic analogue of the natural product pharmacophore. The application of concepts, methodologies and knowledge learned during maturation of the high-throughput paradigm to natural compounds has the potential to increase their contribution for the pharmaceutical industry.