Iron is an essential micronutrient for the survival and growth of living matter. In the context of host-pathogen interactions, they both require iron as a cofactor in proteins involved in energy production, DNA replication, and gene transcription, among many metabolic processes. Although iron is essential for life, excess iron is harmful because it generates reactive oxygen species by Fenton chemistry, which leads to oxidative stress, lipid peroxidation, and cell damage and death. Moreover, normal body physiology requires ferrous iron in minimal amounts. These considerations have served as the driving force behind the evolution of intricate mechanisms that tightly maintain iron homeostasis in mammals. Microbial infections trigger an inflammatory response that leads to host iron sequestration and hypoferremia, often called nutritional immunity. The goal of this innate response, along with other measures that help to sequester host iron, is to limit iron availability to the pathogen as a means of inhibiting pathogen survival, growth, and colonization. To counter host-imposed iron sequestration measures, the pathogen initiates a concerted effort to acquire iron rapidly from different sources within the host using several ingenious strategies. This chapter discusses the epic fight between the host as it attempts to sequester iron and the pathogen as it tries to acquire it.