Nature has been a source of medicinal products for millennia, and during the past century many useful drugs have been developed from natural sources, particularly plants. This review briefly traces the evolution of natural products drug discovery, and outlines the impressive number of important drugs that have originated from natural sources, particularly those related to the treatment of cancer. It is clear that nature will continue to be a major source of new drug leads, and the vast untapped potential of microorganisms is emphasized. With the advent of genetic techniques that permit the isolation and expression of biosynthetic cassettes, microbes and their marine invertebrate hosts may well be the new frontier for natural products lead discovery, although plant endophytes also offer an exciting new resource. Effective drug development will depend on multidisciplinary collaboration embracing natural products lead discovery and optimization through the application of total and diversity-oriented synthesis and combinatorial chemistry and biochemistry, combined with good biology. These factors are illustrated by the impressive number of anticancer drugs, discussed in terms of their mechanisms of action, which are derived from natural sources.