The total synthesis of a series of natural products targeted by virtue of their biological properties are highlighted. Their complex structures inspired the development of new divergent synthetic strategies and synthetic methodology designed especially for the natural products of interest. The subsequent extension to the divergent total syntheses of key analogues that bear deep-seated structural changes are summarized that were used to define the structure-function properties of the natural products, to identify their biological target if unknown, to define fundamental features of their interaction with their biological target, and ultimately to improve their properties, producing supernatural products endowed with features not found expressed by the natural products themselves.