Chronic obstructive pulmonary disease (COPD) is caused mostly by cigarette smoking but its specific molecular mechanisms are obscure. Current theories suggest that the inflammation and oxidative stress induced by smoking lead to proteolytic imbalance and progressive lung structural derangement, with disease susceptibility being controlled by inherited variations in protective or inflammatory genes. However, cigarette smoke is directly mutagenic. Acquired somatic mutations, rather than inherited polymorphisms, might therefore be major determinants of COPD. Somatic mutations in oncogenes such as p53, Ras, EGFR and PTEN abound in the epithelium of smokers. These mutations are persistent, explaining the paradox that smoking cessation does not resolve inflammation. Moreover, the recognition that these somatic mutations converge on key inflammation, host defense and steroid response pathways might help to explain the clinical defects in these processes in COPD and guide discovery of future therapies.