Hypoxia is defined as a decrease in available oxygen reaching the tissues of the body. It is linked to the pathology of cancer, cardiovascular disease, and stroke, the leading causes of death in the United States. Cells under hypoxic stress either induce an adaptive response that includes increasing the rates of glycolysis and angiogenesis or undergo cell death by promoting apoptosis or necrosis. The ability of cells to maintain a balance between adaptation and cell death is regulated by a family of transcription factors called the hypoxia inducible factors (HIF). HIF1, the most widely studied HIF, is essential for regulating the expression of a battery of hypoxia-responsive genes involved in the adaptive and cell death responses. The ability of HIF1 to balance these 2 responses likely lies in the regulation of HIF1α stability and transcriptional activity by post-translational hydroxylation and its ability to respond to other cellular factors including key metabolites and growth factors. Targeting HIF1 signaling for therapeutics, therefore, requires an understanding of how these various signals converge upon HIF1 and regulate its role in maintaining the balance between adaptation and cell death. In addition, one must understand how this balance can be perturbed during toxicant-induced tissue damage. This review will summarize our current understanding of hypoxia signaling as it applies to drug therapy and toxicity and describe how these processes can influence the HIF-mediated balance between adaptation and cell death.