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Re-epithelialization of skin wounds depends upon the mi-gration of keratinocytes from the cut margins of the wound and is enhanced when human keratinocytes are covered with occlusive dressings that induce hypoxia. In this study, two independent migration assays were used to compare cellular motility on connective tissue components under normoxic or hypoxic conditions. Human keratinocytes apposed to col-lagens or fibronectin exhibited increased motility when sub-jected to hypoxic (0.2 or 2 % oxygen) conditions compared with normoxic (9 or 20 % oxygen) conditions. When compared with normoxic cells, hypoxic keratinocytes exhibited increased expression and redistribution of the lamellipodia-associated proteins (ezrin, radixin, and moesin). Furthermore, hypoxic keratinocytes demonstrated decreased secretion of laminin-5, a laminin isoform known to inhibit keratinocyte motility. Hy-poxia did not alter the number of integrin receptors on the cell surface, but did induce enhanced secretion of the 92-kD type IV collagenase. These data demonstrate that hypoxia promotes human keratinocyte motility on connective tissue. Hypoxia-driven motility is associated with increased expres-sion of lamellipodia proteins, increased expression of col-lagenase and decreased expression of laminin-5, the loco-motion brake for keratinocytes.