Lung epithelium is the primary site of lung damage in interstitial lung diseases. Although there are various initiating factors, the terminal stages are characterized by pulmonary fibrosis. Conventional therapy consisting of glucocorticoids or immunosuppressive drugs is usually ineffective. Epithelial cell apoptosis have been considered to be initial events in interstitial lung diseases. The death receptor-mediated signaling pathway directly induces caspase activation and apoptosis. Other stresses induce the release of cytochrome from mitochondria and caspase activation. Endoplasmic reticulum stress also induces apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of the coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymal interaction plays important roles in these processes. Further understanding of apoptosis signaling may lead to effective strategies against devastating lung diseases. We review the role of epithelial cell apoptosis in the molecular mechanisms of pulmonary fibrosis.