While rare MC4R mutations are the commonest cause of monogenic forms of extreme, early-onset obesity, growing evidence shows that common MC4R variants contribute to obesity in the general population. Candidate gene studies have focussed on the V103I and I251L MC4R variants that both affect MC(4) receptor function in vitro. Individual association studies, which are typically small and underpowered, have found no association between V103I (frequency of 103I-allele: ~4%) or I251L (251L-allele: ~2%) and the risk of obesity in the general population. However, large-scale meta-analyses have confirmed that both variants reduce the risk of obesity by -21% in 103I-allele carriers (P<10(-4)) and by -50% in 251L-allele carriers (P<10(-4)). Recently, genome-wide association studies have identified a common variant (minor allele frequency: ~27%) at ~188kb downstream of MC4R showing robust association (P<5×10(-8)) with BMI and obesity in adults and children. Each additional minor allele increases BMI by 0.20kg/m(2), body weight by 700-1000g, and obesity risk by 14% in adults. Interestingly, this variant also showed association with increased height, consistent with the phenotype seen for rare MC4R mutations. Although MC4R is the nearest gene and phenotypic associations are consistent with those of MC4R mutations, it has not yet been established whether this variant indeed reflects MC(4) receptor function. Taken together, common MC4R variants contribute to variation in BMI and obesity risk in the general population. Of particular interest is the finding from genome-wide association studies that suggests that the region downstream of MC4R contributes to its regulation.