Advances in our knowledge of hereditary hemochromatosis (HH) over the past 150 years have revealed new insights into this common genetic disorder. Meticulous family and HLA association studies followed ultimately by cloning of the HFE gene have dramatically changed our understanding of the natural history and manifestations of HH. Cross-sectional studies demonstrated that HH had a highly variable clinical and biochemical penetrance in susceptible individuals of northern European descent.“State-of-the-art” large longitudinal population studies have accurately defined the natural history. We now recognize that HH is not as discreet an entity as previously thought because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical course of HH. While phlebotomy remains the cornerstone of therapy, our diagnostic approach has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches. This review aims to encapsulate this new knowledge in a framework that addresses commonly raised issues relating to the current natural history, diagnosis, and management of HH patients.