During cutaneous wound healing, increased proliferation and migration of epidermal keratinocytes is essential for efficient re-epithelialization of the wound and restoration of barrier function to the skin. Although numerous cell culture studies have identified intracellular signaling proteins that control proliferation and migration in response to extracellular cues from the wound microenvironment, confirming their importance in wound healing requires appropriate in vivo models. The Rho-family guanosine triphosphatase (GTPase) Rac1 is an effector of cellular responses to growth factors, cytokines, and adhesion proteins present in wounds, and it has long been suspected to be an important regulator of wound healing. Two different genetic models now confirm an essential role for Rac1 in wound healing and, further, identify a dual role for Rac1 in promoting keratinocyte migration and proliferation during wound re-epithelialization. This sets the stage for determining which of the known Rac1 pathways are critical for wound repair in vivo and for linking these pathways to specific integrin or growth factor receptors that mediate cellular responses to cues from the wound environment. Together with studies that implicate Rac1 in maintaining epidermal stem cell populations, these findings lay the foundation for identifying distinct epidermal compartments from which Rac1 controls different aspects of wound re-epithelialization.