Hereditary hemochromatosis due to homozygosity for the C282Y mutation in the HFE gene product is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately one in 200. Cross-sectional and longitudinal studies have revealed that clinically significant iron-overload disease develops in at least 28% of male and 1% of female HFE C282Y homozygotes. The relatively low clinical penetrance is largely unexplained. Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of hemochromatosis. Male gender is a strong genetic factor, promoting expression of clinical disease. Dietary intake of alcohol and noncitrus fruit may also act as important environmental modifiers of penetrance. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis are likely to be forthcoming.