Iron is essential to all microorganisms. To obtain iron from the very low concentrations present in their environment, microorganisms have developed sophisticated mechanisms such as the siderophore system. As a primitive defense mechanism, humans have developed mechanisms to withhold iron from microorganisms. Iron-binding proteins such as transferrin, ferritin, and lactoferrin have a central role in human ferrokinetics. These iron-binding proteins also participate in the process of decreasing iron availability for the microorganisms. They do so by decreasing iron reutilization. Anemia of inflammation (previously called anemia of chronic disease) is seen in the setting of infectious, inflammatory, and neoplastic diseases. It results, in part, from changes in the intracellular metabolism of iron. Alterations of iron physiology seen in many clinical circumstances make excess iron available to microorganisms, thus enhancing their pathogenicity. Understanding the molecular basis of iron withholding by the human host, both in the absence of and during infection, and that of iron acquisition by microorganisms may provide us with new and innovative antimicrobial agents and vaccines.