Iron, a versatile electron donor and acceptor, is essential for life as a component of enzymes and oxygen transporters but also has the potential to cause toxicity when in excess. Its dietary absorption as well as plasma and tissue concentrations are subject to close regulation, systemically coordinated by the interaction of the hepatic peptide hormone hepcidin and its cellular receptor, the iron exporter ferroportin. Ferroportin mediates the delivery of iron to plasma from absorptive enterocytes, from macrophages that digest senescent erythrocytes, and from iron-storing hepatocytes. Hepcidin inhibits the transport of iron into plasma by occluding ferroportin and inducing its endocytosis and proteolysis. The production of hepcidin is feedback-regulated by the concentration of extracellular iron, as well as by the amount of iron in hepatic storage. Hepcidin production is also modulated by erythroid regulators (e.g., erythroferrone) that act to match the supply of iron to the fluctuating requirements of hemoglobin synthesis and erythropoiesis. During infections, hepcidin is induced by IL6 and restricts the growth of invading microorganisms by limiting the production of non-transferrin-bound iron. Although many of the underlying molecular and cellular mechanisms have been elucidated through the study of human diseases and their laboratory models, substantial gaps remain to be filled by further investigations.