Hereditary hemochromatosis (HHC) is a condition characterized by excess iron in body tissues, resulting in complications such as cirrhosis, cardiomyopathy, diabetes, and arthritis. These complications usually manifest during adulthood. Two methods of screening for the detection of early stage of HHC are available: serum iron measures and molecular testing to detect mutations in the gene. These phenotypic and genotypic screening tests are of particular interest because a simple treatment-periodic phlebotomy-can be used to prevent iron accumulation and clinical complications. HHC might represent the first adult-onset genetic disorder for which universal population-based screening would be appropriate. Therefore, HHC has been proposed as a paradigm for the introduction of adult genetic diseases into clinical and public health practice. However, universal screening for HHC has not been recommended because of the uncertainty about the natural history of the iron overload or HHC and, in particular, uncertainty about the prevalence of asymptomatic iron overload and the likelihood that it will progress to clinical complications. If universal screening is not appropriate based on current data, what other measures might reduce the disease burden of iron overload? New studies provide more systematic information about the penetrance of the C282Y mutation and shed further light on the natural history of the disorder. The authors review these data and consider their implications for public health, medical genetics, and primary care.