The HIF prolyl hydroxylases PHD1, -2 and -3 regulate the stability of the hypoxia-inducible factors HIF-1a and -2a in an oxygen-dependent manner. Despite the presumed importance of these oxygen sensors, their role in health and disease remains enigmatic. We have generated mice deficient for PHD1, PHD2 and PHD3. PHD2-/- embryos succumbed at mid-gestation (E12.5) showing fatal placentation defects, but PHD1-/- and PHD3-/- mice were healthy and fertile. In order to determine the relative contribution of each PHD to hypoxic tissue responses, PHD-deficient mice were exposed to various pathophysiological conditions leading to tissue hypoxia. We found that femoral artery ligation caused necrosis of skeletal myofibers in PHD2+/­ or PHD3-/- mice, but only negligibly in PHD1-/- mice. Surprisingly, this protection was not due to enhanced angiogenesis, erythropoiesis or glycolysis, but attributable to a reduced production of reactive oxygen species via a HIF-2a-dependent protective genetic program. We conclude that PHD1 is an important regulator of the response to oxidative stress in the skeletal muscle, and that HIF-2a acts as a major effector of PHD1 in the response to oxidative damage.