Astrocytes are increasingly recognized for their impact on neuronal function and viability in health and disease. Hypoxia has Janus-faced influences on astrocytes and their ability to support neuronal viability. For example, hypoxia induces astrocyte-dependent protection of neurons following hypoxia preconditioning. Yet, hypoxia induces processes in astrocytes that augment neuronal death in other situations, such as the coincidence of hypoxia with inflammatory signaling. A complex array of gene expression is induced by hypoxia within astrocytes and neurons through multiple transcription factors and intracellular molecular pathways. The hypoxia inducible factors (HIFs) are transcription factors that are likely instrumental in orchestrating adaptive and pathological functions of astrocytes. As such, the HIFs are postulated to mediate both adaptive and pathological functions during hypoxia/ ischemia. Identifying the conditions under which hypoxia induces signaling in astrocytes that alters autonomous or neuronal survival will undoubtedly have important implications regarding the development of new strategies for stroke treatment.