Aerobic life consumes oxygen for efficient production of high energy compounds. The ability to sense and respond to changes in oxygen partial pressure represents a fundamental property to assure the cellular oxygen supply to be within a narrow range that balances the risks of oxidative damage vs. oxygen deficiency. The discovery of hypoxia-inducible factor-1 (HIF-1) allowed the identification of molecular mechanisms by which changes in oxygenation are transduced to adequate intracellular adaptive responses. It became apparent that hypoxia can initiate cell demise by apoptosis/necrosis but also prevent cell death by provoking adaptive responses that, in turn, facilitate cell proliferation or angiogenesis, thus contributing to tumor progression. Considering that activation of HIF-1 provokes pro-survival as well as pro-death decisions under hypoxia, it will be crucial to understand decision making processes in regulating cell death, adaptation and chemoresistance. Likely, secondary stressors such as pH changes, i.e. acidosis, and the context of genetic alterations will shape the role of HIF-1 to affect susceptibility of cells to undergo hypoxia-induced cell death or to allow adaptation and progression towards malignancy. Understanding the mechanisms by which HIF-1 affects the expression and/or function of key apoptotic regulators such as Bcl-2 family members or p53 will help to uncover how HIF-1 induces cell death and the manner in which cells can overcome such signals and thus determine which of its Janus faces prevail.