The iron overload disorder, hereditary hemochromatosis, is one of the most common genetic diseases of individuals of Northern European descent. The disorder is characterized by the progressive accumulation of dietary iron in the major organs of the body, which if not diagnosed, leads to numerous medical maladies and eventually death. The locus for this disorder was mapped by genetic linkage to the short arm of chromosome over twenty years ago, but it was not until 1996 that the gene for this disorder was cloned by an identity-by-descent positional cloning approach. The gene, called HFE, encodes a major histocompatibility complex (MHC) class I-like protein that is mutated in approx 85% of all individuals known to have hereditary hemochromatosis (HH). Since the cloning of the HFE gene, considerable work has been carried out which has furthered our understanding of the genetics of this prevalent disorder. In addition, with the identification of the transferrin receptor as a protein capable of interacting with HFE we are now beginning to understand how a protein with the structural characteristics of an MHC class I molecule can influence cellular iron homeostasis.