The skin microenvironment is characterized by the extracellular matrix components, soluble molecules produced by neighboring cells but also physicochemical parameters and particularly a very low oxygen level (called physioxia) compared to other organs and the atmosphere. This condition is not taken into account in classical in vitro experiments, which are now replacing animal models for dermocosmetic evaluations. It is now well known that the oxygen level controls the expression of various proteins, either by induction of hypoxia inducible factors (HIFs), or modulation of microRNAs, which are small molecules regulating mRNA transcription. In this review, we focus on both microRNAs regulated by oxygen level and microRNAs involved in the regulation of various skin functions. We highlight the importance of this new concept of skin hysioxia and its consequences on microRNA regulation.