Following the discovery of the HFE gene, it became apparent that C282Y homozygous HFE hemochromatosis is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately 1 in 200. Cross-sectional studies have revealed that the clinical penetrance of symptoms of iron-loading disease is relatively low and highly variable. Although there is no standard definition of clinical penetrance, large studies of newly diagnosed C282Y homozygotes that have specifically assessed liver disease have obtained data showing that penetrance occurs in between 24 and 43% of males and 1 and 14% of females. This 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 HFE hemochromatosis. Currently, the single most important environmental and genetic variables promoting penetrance are alcohol consumption and male gender, respectively. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis await identification.