Hereditary hemochromatosis (HH) is a common autosomal recessive disorder that can result in iron overload and a wide range of clinical complications, including hepatic cirrhosis, diabetes mellitus, hypopituitarism, hypogonadism, arthritis, and cardiomyopathy. People with HH can be detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screening who will develop serious complications of HH is unknown. The genetics of HH may help to resolve these questions. The gene, HFE, and two mutations, C282Y and H63D, have been identified: the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function. Most people with HH are C282Y homozygotes, a small proportion are compound heterozygotes or H63D homozygotes, and some have no identifiable HFE mutation or are HFE heterozygotes, suggesting that additional mutations associated with HH are yet to be found. Gender and environmental agents, such as alcohol and dietary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying factors. HFE mutations also appear to increase the likelihood of iron overload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HH is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene gene and gene environment interactions.