Mammalian cells are believed to have a cell-intrinsic ability to increase glucose metabolism in response to hypoxia. Here we show that the ability of hematopoietic cells to up-regulate anaerobic glycolysis in response to hypoxia is dependent on receptor-mediated signal transduction. In the absence of growth factor signaling, hematopoietic cells fail to express hypoxia-inducible transcription factor (Hif-1α) mRNA. Growth factor-deprived hematopoietic cells do not engage in glucose-dependent anabolic synthesis and neither express Hif-1α mRNA nor require HIF-1α protein to regulate cell survival in response to hypoxia. However, HIF-1α is adaptive for the survival of growth factor-stimulated cells, as suppression of HIF-1α results in death when growing cells are exposed to hypoxia. Growth factor-dependent HIF-1α expression reprograms the intracellular fate of glucose, resulting in decreased glucose-dependent anabolic synthesis and increased lactate production, an effect that is enhanced when HIF-1α protein is stabilized by hypoxia. Together, these data suggest that HIF-1α contributes to the regulation of growth factor-stimulated glucose metabolism even in the absence of hypoxia.