Iron is an essential element in all living organisms and is required as a cofactor for oxygen-binding proteins. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly interconnected. Iron needs to be tightly regulated, as iron insufficiency induces a hypoferric anemia in mammals, coupled to hypoxia in tissues, whereas excess iron is toxic, and causes generation of free radicals. Given the links between oxygen transport and iron metabolism, associations between the physiology of hypoxic response, and the control of iron availability are important. Numerous lines of investigation have proven that the HIF transcription factors function as central mediators of cellular adaptation to critically low oxygen levels in both normal and compromised tissues. Several of these target genes are involved in iron homeostasis, reflecting the molecular links between oxygen homeostasis and iron metabolism.