Primary cilia receive extracellular signals and transmit them to the interior implementing signal transduction. These organelles enable the cell to communicate and realize essential processes such as proliferation and migration. Disruption of primary cilia signaling will lead to a multitude of human diseases called ciliopathies. Ciliopathies are often linked to malformations of the central nervous system. Abnormalities in cilia length are a parameter for inadequate function of primary cilia. Especially in situations when oxygen supply falls short, e.g. during an ischemic stroke, it is necessary to provide relevant signals for counter-regulations quickly, as sufficient oxygen supply is required for proper cell function and survival. Key factors in the hypoxic response are hypoxia-inducible factors (HIFs). Especially HIF-2 promotes neurogenesis and has a protective effect on neuronal stem cells. Through its influence on the formation of new nerve cells and the production of apoptosis inhibitors, HIF-2 is a relevant factor in the regeneration of cerebral pathologies. We now showed, by Immunofluorescence, the localization of hypoxia-inducible factor-2alpha (HIF-2α) in the axoneme of murine neuronal primary cilia under hypoxic conditions. This entails an elongation of the ciliary axoneme, realized by the direct interaction of HIF-2α with the intraflagellar transport protein 88 homolog (IFT88). Quantitative PCR analyses confirmed the induction of Mek1/2, Erk1/2 and associated target genes only in presence of primary cilia and HIF-2α. By increasing MEK/ERK signaling via primary cilia, HIF-2 seems to promote processes to increase the regenerative abilities of the cell and consequently improves the outcome of diseases such as stroke.