We developed an in vitro model of wound reepithelialization based on engineered composite skin equivalents of human keratinocytes. Such organotypic cultures are unique in that regulatory mechanisms of cell growth and differentiation can be investigated under conditions mimicking those in vivo. We employed this model system to evaluate fibrin as a substrate for keratinocyte growth and migration after incisional wounding. Our results show that fibrin decreases the length of the lag phase of keratinocyte activation and increases the consistency of the healing response. In addition, the response of these skin equivalents to wounding mimicks that of animal models in terms of the kinetics of reepithelialization, the spatiotemporal distribution of proliferating cells in and around the wound, the unique phenotype exhibited by the cells in the newly formed epidermis, the upregulation of key molecular anchors that initiate cell migration, and the formation of basement membrane during wound closure. Our results suggest that this model can be used to study molecular mechanisms of reepithelialization and evaluate biomaterials as vehicles for controlled delivery of genes and proteins to promote wound healing.