Diabetics commonly suffer from chronic unresolved wounds with serious effects on morbidity and mortality. While the mechanisms causing poor healing of diabetic wounds are not completely understood, it is clear that measures to improve wound healing in diabetics are desperately needed. Sphingosine kinase 1 (SK1) is an enzyme that generates the bioactive lipid sphingosine 1-phosphate (S1P). SK1 and S1P regulate a diverse range of cellular processes, mainly via the action of five S1P-specific G protein-coupled receptors (S1PRs). This includes cell proliferation, survival, differentiation, migration, and angiogenesis: all processes that are known to be critical in wound healing. Our examination of wound healing in SK1 knockout mice found dramatic defects in the rate of wound resolution in these animals. This, together with our extensive in vitro and in vivo studies have revealed that this signalling enzyme and some of its downstream S1PRs are critical mediators of wound healing in both normal and diabetic settings. Indeed, we found that the application of chemical S1PR agonists, that are currently in the clinic for treatment of multiple sclerosis, resulted in significant improvement in healing of wounds in diabetic (db/db) mice, suggesting the potential to re-purpose these agents. We have also discovered that WISKA, a protein induced by wounding, can activate SK1 and enhance wound healing in mice. Furthermore, we have developed a cell-permeable WISKA peptide that retains the ability to activate SK1, and also found that its application to wounds improved healing in diabetic mice. Thus, our studies to date have aided in understanding the molecular mechanisms controlling wound healing, and also identified new agents to potentially improve diabetic wound healing, of which there is significant current need.