Natural-product-based drug discovery has encountered significant challenges during the past decade. In recent years the pharmaceutical industry has placed low emphasis on natural-product-based drug discovery efforts because of an increasing reliance on newer technologies, such as combinatorial synthesis and high-throughput screening, and their associated approaches to drug discovery. However, recent natural-product-based lead-identifying strategies have successfully and rapidly integrated rational approaches that exploit and evolve the structural diversity provided by nature. These rational approaches include the application of structure- and ligand-based design, relationship building between biosynthetic enzymes and targets as well as within the target and natural product scaffold space, and biology-oriented synthesis-guided library design. This review focuses on the recent clinical and preclinical development of natural-product-based compounds derived from these rational approaches, and is organized according to disease areas as well as novel concepts that may provide a rational basis for future developments.