Signaling by heptahelical G protein-coupled receptors (GPCR) regulates many vital body functions. Consequently, dysfunction of GPCR signaling leads to pathologic states, and approximately 30% of all modern clinical drugs target GPCR. One decade ago, an entire new GPCR family was discovered, which was recently named MAS-related G protein-coupled receptors (MRGPR) by the HUGO Gene Nomenclature Committee. The MRGPR family consists of ∼40 members that are grouped into nine distinct subfamilies (MRGPRA to -H and -X) and are predominantly expressed in primary sensory neurons and mast cells. All members are formally still considered "orphan" by the Committee on Receptor Nomenclature and Drug Classification of the International Union of Basic and Clinical Pharmacology. However, several distinct peptides and amino acids are discussed as potential ligands, including β-alanine, angiotensin-(1-7), alamandine, GABA, cortistatin-14, and cleavage products of proenkephalin, pro-opiomelanocortin, prodynorphin, or proneuropeptide-FF-A. The full spectrum of biologic roles of all MRGPR is still ill-defined, but there is evidence pointing to a role of distinct MRGPR subtypes in nociception, pruritus, sleep, cell proliferation, circulation, and mast cell degranulation. This review article summarizes findings published in the last 10 years on the phylogenetic relationships, pharmacology, signaling, physiology, and agonist-promoted regulation of all MRGPR subfamilies. Furthermore, we highlight interactions between MRGPR and other hormonal systems, paying particular attention to receptor multimerization and morphine tolerance. Finally, we discuss the challenges the field faces presently and emphasize future directions of research.