Cerebral ischemia is the third leading cause of death in industrialized countries and an important health system problem with no efficient treatment to date. The reduction in oxygen and glucose supply triggers a cascade of events such as excitotoxicity, oxidative stress, inflammation, apoptosis, and an adjustment of the gene expression program. The hypoxia inducible factor-1 (HIF-1) is a transcription factor that mediates the adaptive responses to the reduction in oxygen availability. HIF-1 activation in hypoxic conditions promotes the survival of cells through the induction of adaptive genes involved in glucose and energy production, glucose transport, cell proliferation, cell survival, iron homeostasis, erythropoiesis, angiogenesis and vascular reactivity. In recent years, biomedical research has focused on the oxygen regulated α subunit of HIF-1 as a potential therapy in medical events that involve hypoxic conditions. In this review we summarize current knowledge on the use of HIF-1α as a therapeutic target against cerebral ischemia through two different strategies: 1) the use of ischemic preconditioning to induce the HIF-1 pathway regulation, and 2) the pharmacological inhibition of prolyl and asparaginyl hydroxylases. Both strategies appear as attractive options for protection in ischemia in which signaling pathway activation could contribute to the establishment of tolerance in brain.