Hepcidin, an oligopeptide, has two major functions in mammals. Hepcidin regulates iron homeostasis by controlling iron export from absorptive enterocytes, hepatocytes, and macrophages into the circulation via ferroportin inactivation. Hepcidin is also an innate antimicrobial agent that is induced by invasive bacteria, limits bacterial proliferation by reducing iron in plasma and extracellular fluids, and kills bacteria. Herein, we review hepcidin and hepcidin genes, iron acquisition by bacteria, hepcidin actions in mice infected with selected extracellular and intracellular bacteria, and reports of corresponding serious human infections. We discuss the relevance and uncertainties of mouse infection models to understanding serious infection of humans with iron overload by the same bacterial species.