Abstract: G‐protein‐coupled receptors (GPCRs) are the largest known family of cell surface receptors, and they control many important physiological events, including sensory perception, chemotaxis, neurotransmission, and energy homeostasis. However, GPCR signaling can be difficult to study in vivo because of the multitude of GPCRs, the lack of specific synthetic agonists, and the fact that some GPCRs activate multiple signaling pathways. One method to circumvent these problems is to develop an engineered receptor that is unresponsive to its endogenous agonist, yet can be fully activated by synthetic, small‐molecule drugs. Such a receptor, called a receptor activated solely by a synthetic ligand (RASSL), can be rapidly and reversibly activated by a small‐molecule drug and would be a powerful tool to control G‐protein signaling in vivo. Here we present the development of a G_s‐coupled RASSL based on the melanocortin‐4 receptor (MC4R). MC4R couples exclusively to G_s at physiologically relevant concentrations of its endogenous ligand, α‐melanocyte‐stimulating hormone (α‐MSH). Data from human patients and structure‐activity studies have shown that several mutations in MC4R cause a decreased affinity for α‐MSH and can be exploited for RASSL development. Synthetic, small‐molecule agonists of MC4R are now available and can be used to activate mutated receptors in vivo. We are engineering a series of mutations in MC4R to remove the peptide‐binding site while retaining small‐molecule binding and activation. The MC4R G_s RASSL could be used to control many physiological responses associated with G_s signaling such as heart rate, energy homeostasis, and cell proliferation.