Hereditary hemochromatosis (HH) is a disorder associated with progressive iron overload and deposition in multiple organs. It is the most common inherited single gene disorder in people of Northern and Western European descent. About 80% of individuals of European descent with HH are homozygous for a cysteine-to-tyrosine substitution (C282Y) in the gene now called HFE. The function of HFE protein, a major histocompatibility class I-like transmembrane protein, has not been fully elucidated. Three consequences of the C282Y mutation are lack of expression of HFE on the cellular surface, a lowered iron level in macrophages, and an increased rate of clearance of iron from the intestinal lumen. These changes could confer protection against certain pathogens early in life before iron overload occurs. Furthermore, the C282Y mutation might have been selected for during the European plagues caused by Yersinia spp. and other pathogens because of the conferred resistance to infection, i.e., by epidemic pathogenic selection.