Pathological remodeling of the airway epithelium is commonly observed in cystic fibrosis (CF). Thus, tissue repair is critical to restore integrity and maintenance of the epithelial barrier function. Epithelial repair is a multi-step process initiated by progenitor cell migration into the injured area, proliferation, and re-differentiation into all of the cell types that contribute to the function of a normal airway epithelium. Recent technological advances applied to relevant animal and cell injury models have helped in understanding the complexity of progenitor cell differentiation. This short review will introduce the current knowledge of the mechanisms regulating airway epithelial cell (AEC) regeneration and repair, with a focus on the specification of two rare cell types/states: ionocytes and deuterosomal cells.