Keratinocytes freshly isolated from unwounded skin could not attach and spread on fibronectin (FN)-coated culture dishes and could not bind and phagocytose FN-coated beads. These adhesive functions were activated, however, in keratinocytes that were isolated from healing wounds. Moreover, adhesiveness of basal keratinocytes to FN substrata was activated during epidermal cell or explant culture. Activation was specific for attachment to FN compared to other adhesion ligands, and occurred even when epidermal cells were cultured on collagen, basement membrane matrix, or lectin-coated substrata. Biochemical studies showed that keratinocytes have a 140×103Mr FN receptor analogous to the fibroblast receptor for FN, and that this receptor is expressed in activated keratinocytes but not in keratinocytes freshly isolated from unwounded skin. The absence of FN receptors from keratinocytes in unwounded skin is not surprising since the basal keratinocytes of the epidermis are attached to a basement membrane containing laminin and type IV collagen. During wound repair, however, these cells migrate over or through a FN-coated matrix. Consequently, expression of FN receptors may be an essential feature of healing. Believing that FN is the required substratum for keratinocyte migration during wound healing, we have initiated clinical studies to determine if topical application of FN is useful as a therapy for non-healing cutaneous ulcers.