Deprivation of oxygen (hypoxia) and/or glucose (hypoglycemia) represents a serious stress that affects cellular survival. The hypoxia-inducible transcription factor-1α (HIF-1α), which has been implicated in the cellular response to hypoxia (Semenza, G. L. (1999) Annu. Rev. Cell Dev. Biol. 15, 551-578), mediates apoptosis during hypoxia (Halterman, M. W., Miller, C. C., and Federoff, H. J. (1999) J. Neurosci. 19, 6818-6824 and Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., Koch, C. J., Ratcliffe, P., Moons, L., Jain, R. K., Collen, D., and Keshet, E. (1998) Nature 394, 485-490), but the function of its homologue HIF-2α remains unknown. Therefore, the role of HIF-2α in cellular survival was studied by targeted inactivation of the HIF-2α gene (HIF-2α-/-) in murine embryonic stem (ES) cells. In contrast to HIF-1α deficiency, loss of HIF-2α did not protect ES cells against apoptosis during hypoxia. Both HIF-1α -/- and HIF-2α-/- ES cells were, however, resistant to apoptosis in response to hypoglycemia. When co-cultured with wild type ES cells, HIF-2α-/- ES cells became rapidly and progressively enriched in hypoglycemia but not in hypoxia. Thus, HIF-1α and HIF-2α may have distinct roles in responses to environmental stress, and despite its name, HIF-2α may be more important in the survival response to environmental variables other than the level of oxygen.