The constant intrinsic and extrinsic stress the skin is exposed to leads to significant impairments of the regenerative capacity of aging skin. Current skin rejuvenation approaches lack the ability to holistically support the biological processes that exhaust during aging skin degeneration, such as collagen production, cell migration and proliferation, and new vessel formation. Similar to chronic wounds, aged skin is characterized by dysfunction of key cellular regulatory pathways impairing regeneration. Recent evidence suggests that the same mechanisms hindering a physiologic healing response in chronic wounds are the basis of impaired tissue homeostasis in aged skin. Dysfunction of a main response-to-injury pathway, the hypoxia-inducible factor (HIF)-1α regulatory pathway, has been identified as pivotal both in chronic wounds and in aging skin degeneration. HIF-1α signaling is significantly involved in tissue homeostasis and neovascularization, resulting in the production of new collagen, elastin, and nourishing blood vessels. Modulating the functionality of this pathway has been demonstrated to significantly enhance tissue regeneration. In this review, we present an overview of the regenerative effects linked to the up-regulation of HIF-1α functionality, potentially resulting in skin rejuvenation on both the cellular level and the tissue level.