Physiological brain function is highly dependent on regular oxygen and glucose supply. Reduced oxygen partial pressure or hypoxia has been associated with a number of central nervous system pathologies such as stroke, vascular malformation or neurodegenerative disorders. Whether hypoxia is the cause or the consequence of the disease, and if hypoxia is rather protective or detrimental for neuronal survival, is still unclear. The central regulators of oxygen-dependent gene transcription are the heterodimeric hypoxia inducible factors (HIFs). In normoxia, a family of prolyl-4-hydroxylase domain (PHD) proteins hydroxylates the HIF??subunits which leads to their degradation via the ubiquitin-proteasome pathway. While severe hypoxia elicits neuronal cell death, a decrease in cellular oxygen partial pressure also induces the expression of vascular endothelial growth factor (VEGFA) and erythropoietin (EPO) which protect neurons from ischemic cell death and improve cognitive function. Therefore, PHDs have been suggested to be attractive targets for neuroprotection after stroke. Previous studies showed that pharmacological PHD inhibitors and neuron-specific ablation of PHD2 can reduce acute neuronal damage in animal models of experimental stroke by induction of the HIF pathway. Furthermore, iron-chelating drugs, well-known as PHD-inhibitors, have been shown to upregulate HIF and HIF-target genes and are currently evaluated as therapeutic agents in Alzheimer's disease (AD). Along the same line, we identified presenilins, known to be involved in the pathogenesis of AD, as novel regulators of the PHD/HIF signaling pathway by two distinct mechanisms. Despite decreased PHD2 protein levels, we found lower HIF? levels in presenilin-deficient cell lines and brain tissues. Intriguingly, PSEN1/2 mutations identified in AD patients differentially affected the hypoxic response. Despite thorough research to better understand PHD function in the neuronal system, many questions still remain unclear. Though intriguing, terapeutic intervention should therefore be employed with caution and might require a well-balanced adjustment of the PHD/HIF system rather than simple PHD blockage.