Efficient repair of the epithelial tissue, which is frequently exposed to insults, is necessary to maintain its functional integrity. It is therefore necessary to better understand the biological and molecular determinants of tissue regeneration and to develop new strategies to promote epithelial repair. Interestingly, a growing body of evidence indicates that many members of the large and widely-expressed family of K⁺ channels are involved in the regulation of cell migration and proliferation, key processes of epithelial repair. The first goal of this review is to briefly summarize the complex mechanisms, including cell migration, proliferation and differentiation, engaged after epithelial injury. We then present evidence implicating K⁺ channels in the regulation of these key repair processes. The mechanisms whereby K⁺ channels may control epithelial repair processes are also described. In particular, changes in membrane potential, K⁺ concentration, cell volume, intracellular calcium and signaling pathways following modulation of K⁺ channel activity, as well as physical interaction of K⁺ channels with the cytoskeleton or integrins are presented. Finally, the challenges to efficient, specific and safe targeting of K⁺ channels for therapeutic applications to improve epithelial repair in vivo are discussed.