The iron hormone hepcidin and its receptor and cellular iron exporter ferroportin control the major fluxes of iron into blood plasma: intestinal iron absorption, the delivery of recycled iron from macrophages, and the release of stored iron from hepatocytes. Because iron losses are comparatively very small, iron absorption and its regulation by hepcidin and ferroportin determine total body iron content. Hepcidin is in turn feedback-regulated by plasma iron concentration and iron stores, and negatively regulated by the activity of erythrocyte precursors, the dominant consumers of iron. Hepcidin and ferroportin also play a role in host defense and inflammation, and hepcidin synthesis is induced by inflammatory signals including interleukin-6 and activin B. This review summarizes and discusses recent progress in molecular characterization of systemic iron homeostasis and its disorders, and identifies areas for further investigation.