Cutaneous injury causes underlying tissue damage that must be quickly repaired to minimize exposure to pathogens and to restore barrier function. While the role of growth factors in tissue repair is established, the role of lipid mediators in skin repair has not been investigated extensively. Using a mass spectrometry-based lipid mediator metabolomics approach, we identified D-series resolvins and related pro-resolving lipid mediators during skin injury in mice and pigs. Differentiation of human epidermal keratinocytes increased expression of 15-lipoxygenase and stereospecific production of 17S-hydroxydocosahexaenoic acid, the common upstream biosynthetic marker and precursor of D-series resolvins. In human and pig skin, specific receptors for D-series resolvins were expressed in the epidermal layer and mice deficient in RvD1 receptor Alx/Fpr2 showed an endogenous defect in re-epithelialization. Topical application of D-series resolvins expedited re-epithelialization during skin injury and they enhanced migration of human epidermal keratinocytes in a receptor-dependent manner. The enhancement of re-epithelialization by RvD2 was lost in mice genetically deficient in its receptor and migration of keratinocytes stimulated with RvD2 was associated with activation of the PI3K-AKT-mTOR-S6 pathway, blockade of which prevented its pro-migratory actions. Collectively, these results demonstrate that resolvins have direct roles in the tissue repair program.