Hereditary hemochromatosis has been redefined over the past century, from a rare (but often fatal) disorder of iron overload known as "bronzed diabetes" to only biochemical evidence of altered iron metabolism, and recently to mere expression of the C282Y homozygous genotype of the HFE gene. The variable definitions of the disease, as well as the variable degree of penetrance of the C282Y homozygous genotype, have made it difficult to determine optimal screening strategies. Multiple studies performed since discovery of the C282Y mutation have led to the conclusion that overall penetrance of the genotype is low and that screening of asymptomatic general populations for hereditary hemochromatosis is not recommended. Screening for HFE mutations among certain patient groups, including patients with cirrhosis, however, may help target those who would benefit most from iron removal. For most patients, phlebotomy is the preferred treatment option; iron chelation therapies are available for patients unable to tolerate phlebotomy.