CAR (CARSKNKDC) is a systemically administered wound-homing peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury. CAR peptide requires heparan sulfate proteoglycans (HSPGs) for its cell penetrating activity. Syndecan-4 (SDC4) is a HSPG and binding to it triggers the wound re-epithelialization process. We have discovered that CAR peptide has the inherent ability to promote wound healing; wounds close and re-epithelialize significantly faster in CAR treated mice than in control groups (PBS and mutant peptide, i.e. mCAR injections). To delineate the molecular mechanism by which CAR accelerates wound healing, we focused on the requirement of HSPG binding for CAR peptide function. We demonstrate that CAR peptide endocytosis and its stimulation of keratinocyte cell migration are both dependent on SDC4. Finally, we show that the systemic administration of CAR peptide stimulates wound re-epithelialization only in WT mice, but not in SDC4 knockout (KO) mice. As SDC4 has very restricted expression in skin wounds, we propose that CAR peptide activates SDC4 function to promote re-epithelialization. CAR peptide may provide an entirely new way of enhancing wound healing, and perhaps tissue regeneration in general. This therapeutic approach is systemic, yet target organ- and cell- specific, and dependent on the naturally occurring SDC4 dependent migratory pathway that is crucial for tissue regeneration.