Keratinocytes are the major cellular component of epidermis, and they have several critical roles in the wound healing process. They are involved in the intricate mechanisms of initiation, maintenance, and completion of wound healing. The properties of keratinocytes vary depending upon their location and circumstances within chronic wounds. Keratinocytes at the non-healing edges of chronic wounds differ from normal, healthy keratinocytes. The cross-talk between healthy keratinocytes and other cell types participating in wound healing is critical for successful wound closure. This discovery provides the biological foundation for debridement: Removing "bad" cells from a quiescent wound edge and exposing or even replacing them with "healthy" cells with a high regenerative potential can enhance epithelialization and healing of chronic wounds. This paper will review the biological and pathological properties of keratinocytes as they relate to wound healing, and the ways in which they may provide highly efficacious therapy for patients with chronic wounds.