Maintaining physiologic iron concentrations in tissues is critical for metabolism and host defense. Iron absorption in the duodenum, recycling of iron from senescent erythrocytes, and iron mobilization from storage in macrophages and hepatocytes constitute the major iron flows into plasma for distribution to tissues, predominantly for erythropoiesis. All iron transfer to plasma occurs through the iron exporter ferroportin. The concentration of functional membrane-associated ferroportin is controlled by its ligand, the iron-regulatory hormone hepcidin, and fine-tuned by regulatory mechanisms serving iron homeostasis, oxygen utilization, host defense, and erythropoiesis. Fundamental questions about the structure and biology of ferroportin remain to be answered. Drakesmith et al. discuss the regulation of ferroportin, the sole known vertebrate cellular iron exporter. Systemic iron homeostasis and its responses to hemorrhage and infection depend mainly on posttranslational regulation of ferroportin by its ligand hepcidin, but local factors also modulate ferroportin expression. Dysregulation of ferroportin causes important iron disorders.