Chronic obstructive pulmonary disease (COPD) is a disease involving airways restriction, alveolar destruction, and loss of lung function, primarily due to cigarette smoke (CS) exposure. The inducible stress protein heme oxygenase-1 (HO-1) has been implicated in cytoprotection against the toxic action of many xenobiotics, including CS. HO-1 also protects against elastase-induced emphysema. Differential expression of HO-1 in epithelial cells and macrophages may contribute to COPD susceptibility. Genetic polymorphisms in the HO-1 gene, which may account for variations in HO-1 expression among subpopulations, may be associated with COPD pathogenesis. Carbon monoxide (CO), a primary reaction product of HO-1 has been implicated in cytoprotection in many acute lung injury models, though it's precise role in chronic CS-induced lung injury remains unclear. CO is a potential biomarker of CS exposure and of inflammatory lung conditions. To date, a single clinical trial has addressed the possible therapeutic potential of CO in COPD patients. The implications of the cytoprotective potential of HO-1/CO system in CS-induced lung injury and COPD are discussed.