Genomic studies of leucine-rich repeat containing G proteincoupled receptors from diverse species have indicated that LGRs can be subdivided into three Z-VAD-FMK groups. The ligands for the group A and group C LGRs are glycoprotein hormones and relaxin/insulin-like peptides, respectively. Intriguingly, several studies have demonstrated that the group B LGRs are able to OSI-774 EGFR/HER2 inhibitor interact with R-spondins, whereas our recent study has shown that they are also able to bind to bursicon-like molecules such as bursicon and norrin. The mammalian group B LGRs have recently gained prominence as potential stem cell markers and they seem to play crucial roles in maintaining stem cell functions in diverse tissues. For example, LGR4 is required for maintenance of stem cells in the intestine, mammary gland and prostate. LGR5 is a marker of stem cells located in the crypts of the gastrointestinal tracts, the nascent nephrons of the kidney, and the hair follicles. LGR6-positive stem cells in the hair follicles have been found to be capable of generating all cell lineages of the skin. In addition to their vital roles in stem cells, studies using mutant animal models have also shown that the group B LGRs are essential during mammalian development. For example, it has been demonstrated that the Lgr4 gene displays a very wide expression, with stronger signals being present in the kidney, adrenal gland, bone/cartilage, gastrointestinal tracts, heart, reproductive tracts and nervous systems. As a result of this wide distribution, the phenotypes of Lgr4-null mice are quite complicated. Disruption of the Lgr4 gene in mice on the C57B1/ 6J x Swiss Webster background led to perinatal lethality and intrauterine growth retardation; these effects were associated with pronounced decreases in the weights of the kidney and liver. In contrast, Lgr4-null mice that have a CD1 background are viable; nevertheless, male Lgr4-null mice are sterile and have a number of major defects affecting their reproductive tracts; these include the dilated rete testis and absence of sperms in the epididymis.