Iron is an essential trace metal for nearly all infectious microorganisms, and host defense mechanisms target this dependence to deprive microbes of iron. This review highlights mechanisms that are activated during infections to restrict iron on mucosal surfaces, in plasma and extracellular fluid, and within macrophages. Iron overload disorders, such as hereditary hemochromatosis or β-thalassemia, interfere with iron-restrictive host responses, and thereby cause increased susceptibility to infections with microbes that can exploit this vulnerability. Anemia of inflammation (formerly known as anemia of chronic diseases) is an “off-target” effect of host defense wherein inflammatory cytokines shorten erythrocyte lifespan by activating macrophages, prioritize leukocyte production in the marrow, and induce hepcidin to increase plasma transferrin saturation and the concentration of non-transferrin-bound iron.