The airway surface epithelium is frequently injured by microorganisms and viruses due to its permanent contact with the external medium. Following injury, the epithelium is able to repair itself and regenerate through several mechanisms including spreading and migration of basal cells, cell proliferation and differentiation. The cellular and molecular factors involved in wound repair and epithelial regeneration interact closely, implying the participation of cytoskeleton proteins and integrins receptors, matrix metalloproteinases and their inhibitors as well as cytokines and growth factors secreted by airway epithelial and mesenchymal cells. The spatio-temporal modulation of the pro-inflammatory cytokines such as IL-8, and MMPs (MMP-9 and -7) during the different steps of regeneration suggests that the matrix and secretory environment are markedly involved in these mechanisms and that their dysregulation may induce remodeling of the airway mucosa. A better knowledge of the mechanisms involved in airway epithelium regeneration may pave the way to regenerative therapeutics allowing the reconstitution of a functional airway mucosa in numerous respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary diseases and bronchiolitis.