Iron is required for efficient oxygen transport, and hypoxia signaling links erythropoiesis with iron homeostasis. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low levels of O2. One component of this pathway, hypoxia-inducible factor (HIF), is a transcription factor that is highly active in hypoxic cells. The first HIF target gene characterized was EPO, which encodes erythropoietin-a glycoprotein hormone that controls erythropoiesis. In the past decade, there have been fundamental advances in our understanding of how hypoxia regulates iron levels to support erythropoiesis and maintain systemic iron homeostasis. We review the cell type-specific effects of hypoxia and HIFs in adaptive response to changes in oxygen and iron availability as well as potential uses of HIF modulators for patients with iron-related disorders.