A dynamic interplay between the host and pathogen determines the course and outcome of infections. A central venue of this interplay is the struggle for iron, a micronutrient essential to both the mammalian host and virtually all microbes. The induction of the ironregulatory hormone hepcidin is an integral part of the acute phase response. Hepcidin switches off cellular iron export via ferroportin-1 and sequesters the metal mainly within macrophages, which limits the transfer of iron to the serum to restrict its availability for extracellular microbes. When intracellular microbes are present within macrophages though, the opposite regulation is initiated because infected cells respond with increased ferroportin-1 expression and enhanced iron export as a strategy of iron withdrawal from engulfed bacteria. Given these opposing regulations, it is not surprising that disturbances of mammalian iron homeostasis, be they attributable to genetic alterations, hematologic conditions, dietary iron deficiency or unconsidered iron supplementation, may affect the risk and course of infections. Therefore, acute, chronic or latent infections need to be adequately controlled by antimicrobial therapy before iron is administered to correct deficiency. Iron deficiency per se may negatively affect growth and development of children as well as cardiovascular performance and quality of life of patients. Of note, mild iron deficiency in regions with a high endemic burden of infections is associated with a reduced prevalence and a milder course of certain infections which may be traced back to effects of iron on innate and adaptive immune function as well as to restriction of iron for pathogens. Finally, absolute and functional causes of iron deficiency need to be differentiated, because in the latter form, oral iron supplementation is inefficient and intravenous application may adversely affect the course of the underlying disease such as a chronic infection. This chapter summarizes our current knowledge on the regulation of iron metabolism and the interactions between iron and the immune response against microbes. Moreover, some of the unanswered questions on the association of iron administration and infections are addressed.