Significance: Eicosanoids are biologically active lipid mediators derived from arachidonic acid that are important in injury and inflammatory responses. Cyclooxygenase-1 and cyclooxygenase-2 mediate the production of prostanoids, whereas 5-lipoxygenase mediates the production of leukotrienes and hydroxyeicosatetraenoic acids. These lipid mediators have traditionally been known to recruit cells of the immune system to a site of injury and inflammation. However, they also interact with various cells that are resident to the wound bed, including modulation of keratinocyte activity. Recent Advances: Recent work has identified multiple prostanoid and leukotriene receptors on keratinocytes, indicating that eicosanoids directly interact with them. Recent work also shows that keratinocytes are capable of producing prostanoids and leukotrienes. Critical Issues: Much of the critical work has been performed in cell culture and mouse in vivo models. This has greatly expanded our understanding of the eicosanoid interactions with keratinocytes and wound healing in general. However, few of these in vivo models have been able to critically evaluate keratinocyte migration and re-epithelialization. Future Directions: As research continues in this exciting field, the cellular pathways stimulated by the eicosanoids will become better defined. Future research with excisional wound models in mice and pigs and ex vivo human skin models will better isolate the contribution of eicosanoid-mediated effects on keratinocyte migration and re-epithelialization.