The calcium-dependent cytosolic, neutral, thiol endopeptidases, calpains, perform limited cleavage of their substrates thereby irreversibly changing their functions. Calpains have been shown to be involved in several physiological processes such as cell motility, proliferation, cell cycle, signal transduction, and apoptosis. Overactivation of calpain or mutations in the calpain genes contribute to a number of pathological conditions including neurodegenerative disorders, rheumatoid arthritis, cancer, and lung diseases. High concentrations of reactive oxygen and nitrogen species (RONS) originated from cigarette smoke or released by numerous cell types such as activated inflammatory cells and other respiratory cells cause oxidative and nitrosative stress contributing to the pathogenesis of COPD. RONS and calpain play important roles in the development of airway and pulmonary vascular remodeling in COPD. Published data show that increased RONS production is associated with increased calpain activation and/or elevated calpain protein level, leading to epithelial or endothelial barrier dysfunction, neovascularization, lung inflammation, increased smooth muscle cell proliferation, and deposition of extracellular matrix protein. Further investigation of the redox-dependent calpain signaling may provide future targets for the prevention and treatment of COPD.