Erythropoietin (Epo) regulates red cell production in response to tissue oxygenation. Hypoxia, the main physiological stimulus of enhanced Epo gene transcription, can induce several 100-fold increases in circulating serum Epo levels mediated by hypoxia-inducible factor (Hif). Kapitsinou and colleagues ablated Hif-2α in the kidney and partially in the liver. They found that hypoxic induction of Epo is completely Hif-2–dependent and that in the absence of renal Hif-2, hepatic Hif-2 takes over as the main regulator of the serum Epo response to hypoxia. Their report corroborates recent genetic studies in mice and investigations of patients with familial erythrocytosis which have provided strong evidence that HIF-2α, not HIF-1α, is the prevalent regulator of circulating Epo levels. The image provided is a composite of the liver, kidney, and bone and RBC images as follows: liver image,¹¹  kidney image,¹²  and bone and RBC image.¹³