Hypoxia-inducible transcription factors (HIF)-1 and HIF-2, composed of an oxygen-dependent alpha-subunit and a constitutive beta-subunit, have been characterized as the most important regulators of oxygen homeostasis during physiological and pathological conditions. During embryonic, fetal and postnatal brain development, HIFs and specific HIF target genes are involved in early and highly active maturational processes by modulating cell differentiation, vascular development, angiogenesis and metabolic homeostasis. Under hypoxic conditions, activation of the HIF system reflects an immediate and cell-specific response to acute brain hypoxia. In a complementary fashion, both HIF-1 and HIF-2 modulate cerebral hypoxic stress responses and activate endogenous neuroprotective systems during acute and late stages of hypoxic/ischemic (HI) damage of the developing brain. Therefore, HIFs and their specific target genes that are expressed during brain injury are of particular interest for future diagnostic and therapeutic options in HI injury of the developing nervous system.