Dysregulation of systemic iron homeostasis affects over a billion people worldwide. In patients with hereditary hemochromatosis and β-thalassemia the excess tissue iron is the major cause of many serious complications and can even prove fatal. Although these are distinct diseases they demonstrate intestinal hyperabsorption of iron. Our recent publications using genetic mouse models and cell lines have shown that the transcription factor hypoxia-inducible factor (HIF)2a is a critical regulator of iron absorption. Disruption of HIF2a signaling in the intestine results in low systemic iron and hematological defects, whereas a chronic increase in HIF2a signaling leads to iron overload. Recently, in animal models of iron overload, such as hereditary hemochromatosis and β-thalassemia, we demonstrate that HIF2a signaling is activated. These are critical findings since alternatives to current treatments of iron overload are a high priority. Building on our recent data, we propose to identify mechanisms by which iron absorption is increased and assess the utility of HIF2a as a therapeutic target in iron overload disorders.