Covering: 2000 to 2019The discovery of new natural products that have some combination of unprecedented chemical structures, biological activities of therapeutic interest for urgent medical needs, and new molecular targets provides the fuel that sustains the vitality of natural products chemistry research. Unfortunately, finding these important new compounds is neither routine or trivial and a major challenge is finding effective discovery paradigms. This review presents examples that illustrate the effectiveness of a chemical genetics approach to marine natural product (MNP) discovery that intertwines compound discovery, molecular target identification, and phenotypic response/biological activity. The examples include MNPs that have complex unprecedented structures, new or understudied molecular targets, and potent biological activities of therapeutic interest. A variety of methods to identify molecular targets are also featured.