The term hemochromatosis refers to a group of genetic disorders characterized by hepcidin insufficiency in the context of normal erythropoiesis, iron hyperabsorption, and expansion of the plasma iron pool with increased transferrin saturation, the diagnostic hallmark of the disease. This results in the formation of toxic non–transferrin-bound iron, which ultimately accumulates in multiple organs, including the liver, heart, endocrine glands, and joints. The most common form is HFE-hemochromatosis (HFE-H) due to p.Cys282Tyr (C282Y) homozygosity, present in nearly 1 in 200 people of Northern European descent but characterized by low penetrance, particularly in females. Genetic and lifestyle cofactors (especially alcohol and dysmetabolic features) significantly modulate clinical expression so that HFE-H can be considered a multifactorial disease. Nowadays, HFE-H is mostly diagnosed before organ damage and is easily treated by phlebotomy, with an excellent prognosis. After iron depletion, maintenance phlebotomy can be usefully transformed into a blood donation program. Lifestyle changes are important for management. Non-HFE-H, much rarer but highly penetrant, may lead to early and severe heart, liver, and endocrine complications. Managing severe hemochromatosis requires a comprehensive approach optimally provided by consultation with specialized centers. In clinical practice, a proper diagnostic approach is paramount for patients referred for hyperferritinemia, a frequent finding that reflects hemochromatosis only in a minority of cases.