The neurodegeneration and anemia of Irp2-/- mice and the polycythemia and pulmonary hypertension of Irp1-/- mice underline the essential role of IRP/IRE machinery in regulating cellular and systemic iron homeostasis, and also suggest that mutations of IRP1 and IRP2 could underlie some human diseases. The gene discussed is IREB2; the disease is pulmonary hypertension.