Abstract: Hypoxia-inducible factors (HIFs) are transcriptional regulators playing important roles in adapting various types of cells to physiological and pathological hypoxia cues. Three structurally related, oxygen-sensitive HIFα proteins have been identified (HIF1α, HIF2α, and HIF3α), among which HIF3α has weak transcriptional capacity because of the absence of the C-terminal transactivation domain as present in HIF1α and HIF2α. The role of HIFα in regulating diverse biological processes is primarily through the actions of its downstream target genes and/or signaling pathways (Figure 1). The HIFα signaling is subjected to regulation at the multiple levels as detailed in Figure 1. Previous studies have shown that HIF1α and HIF2α activate both common (canonical) and distinct (non-canonical) sets of target genes in cell-type and context dependent manners. The importance of HIFα (HIF1α and HIF2α) in embryonic development is manifested by the lethality of early embryos or neonates of HIF1α–/– mice and HIF2α–/– mice due to the cardiovascular and lung malformation. In the developing central nervous system (CNS) where the maturation of the vascular network is still ongoing, the local oxygen concentration ranges from 0.5% to 7% (Ivanovic, 2009). The physiologically hypoxic environment in the CNS suggests that HIFα may play an important role in neural development.