Wound re-epithelialization represents a tissue movement that crucially participates in wound closure. Recently, we demonstrated that supplemented leptin improved re-epithelialization processes in leptin-deficient ob/ob mice. In this study we investigated regulation of the leptin system during normal repair in healthy animals. We found leptin to be present at the wound site during healing, although leptin levels were clearly reduced upon injury compared with uninvolved control skin. The functional leptin receptor subtype obRb was observed to be constitutively expressed in nonwounded skin. During early healing, the leptin receptor obRb was downregulated, but re-increased again from day 5 postwounding. Immunohistochemistry revealed that highly proliferative keratinocytes of the wound margin epithelia strongly expressed the functional leptin receptor subtype obRb. In vitro studies demonstrated that murine and human primary epidermal keratinocytes responded to exogenously added leptin with a proliferative response. Moreover, specificity of leptin-mediated mitogenic effects on primary keratinocytes could be shown by completely blocking leptin actions by a soluble, nonfunctional chimeric leptin receptor. Finally, we report that leptin, besides the recently described activation of the janus tyrosine kinase signal transducers, also activated extracellular signal-regulated kinase-controlled signaling pathways in primary keratinocytes.