Covering: up to April 2021The bacterial cyclic depsipeptides FR900359 (FR) and YM-254890 (YM) were shown to selectively inhibit Gαq proteins with high potency and selectivity and have recently emerged as valuable pharmacological tools due to their effective mechanism of action. Here, we summarize important aspects of this small and specialized natural product family, for which we propose the name chromodepsins, starting from their discovery, producing organisms and structural variety. We then review biosynthesis, structure-activity relationships and ecological and evolutionary aspects of the chromodepsins. Lastly, we discuss their mechanism of action, potential medicinal applications and future opportunities and challenges for further use and development of these complex inhibitor molecules from nature.