Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Iron overload represents a significant risk factor in the development of HCC. Hereditary hemochromatosis (HH) is a genetic iron overload disease characterized by hepatic iron accumulation. The potential link between these two conditions leads to significant curiosity about regulation of iron homeostasis. Importantly, one of the HH genes, HAMP, encodes the master regulator of iron homeostasis, hepcidin, which is expressed by hepatocytes. Recent studies have shown that the remaining HH genes are either upstream regulators (HFE, HFE2 and TFR2) or downstream targets (FPN) of hepcidin. Moreover, the presence of additional signaling pathways in the liver that contribute to regulation of hepcidin expression has been documented. The function of these iron-regulatory proteins is currently being investigated to determine if they play a role in abnormal iron uptake in tumors. This review summarizes these recent studies and briefly discusses new directions in the treatment of iron overload in HCC patients.