While survival from stroke, traumatic brain and spinal cord injuries, neurodegenerative diseases and hypoxia has improved over the past several years, treatments are limited and impacts of these injuries and diseases to patients, families and society can be devastating. Recovery from these injuries is variable and involves in part an orchestrated angiogenesis and neurogenesis in the neurogenic zones (neurovascular niches) of the CNS. In this focused review the roles of HIF-1alpha mediated responses to hypoxia in CNS neurovascular niches is discussed. Using in vivo and in vitro murine models of sublethal hypoxia we mimicked the variable responses observed in the human population and correlated differences in baseline and hypoxia-induced induction of HIF-1alpha and several downstream signaling components including BDNF, VEGF, SDF-1, TrkB, Nrp-1, CXCR4 and NO with differences in survival as well as endothelial cell and neural stem cell survival and proliferation, providing insight into this important and timely problem and suggesting that optimization of expression levels of some or all of these signaling components may have the potential of maximizing recovery following CNS injury.