Significance: Integrins are bidirectional signaling receptors for extracellular matrix that regulate both inside-out signaling that controls keratinocyte-mediated changes to the wound microenvironment and outside-in signaling that controls keratinocyte responses to microenvironmental changes. As such, integrins represent attractive therapeutic targets for treatment of chronic wounds or general promotion of wound healing. Advances in wound management are particularly important as the elderly and diabetic populations within the United States continue to grow. Recent Advances: Although integrins are best known for mediating cell adhesion and migration, integrins in wound epidermis also control cell survival, proliferation, matrix remodeling, and paracrine crosstalk to other cellular compartments of the wound. Importantly, the concept of targeting integrins in the clinic has been established for treatment of certain cancers and other diseases, laying the groundwork for similar exploitation of integrins as targets to treat chronic wounds. Critical Issues: Despite their attractiveness as therapeutic targets, integrins have complex roles in wound healing that are impacted by both their own expression and a highly dynamic wound microenvironment that determines ligand availability. Therefore, identifying relevant integrin ligands in the wound and understanding both distinct and overlapping functions that different integrins play in the epidermis will be critical to determine their precise roles in wound healing. Future Directions: Future research should focus on gaining a thorough understanding of the highly coordinated functions of different integrins in wound epidermis, and on determining which of these functions go awry in pathological wounds. This focus should facilitate development of integrin-targeting therapeutics for treating chronic wounds.