For several years, drugs with reactive electrophilic appendages have been developed. These units typically confer prolonged residence time of the drugs on their protein targets, and may assist targeting shallow binding sites and/or improving the drug-protein target spectrum. Studies on natural electrophilic molecules have indicated that, in many instances, natural electrophiles use similar mechanisms to alter signaling pathways. However, natural reactive species are also endowed with other important mechanisms to hone signaling properties that are uncommon in drug design. These include ability to be active at low occupancy and elevated inhibitor kinetics. Herein, we discuss how we have begun to harness these properties in inhibitor design.