Prohormone convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is a serine endoprotease involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1, exhibit a variable and pleiotropic syndrome mainly consisting of obesity, malabsorptive diarrhea, and other endocrinopathies. The majority of the PCSK1 null patients suffer from early-onset obesity and hyperphagia. Furthermore, nearly 1% of extremely obese Europeans exhibit rare heterozygous PCSK1 mutations that result in partial loss of PC1/3 activity and are associated with profound effects on metabolism. Despite not displaying the complex endocrine phenotype of PC1/3-deficient subjects, carriers of these mutations exhibit an 8.7-fold increased risk of obesity over subjects lacking these mutations. In addition to rare PCSK1 variants, numerous genome-wide association studies (GWAS) show a convincing association between certain polymorphisms in the PCSK1 gene that are common in the population and increased risk of obesity.