Lung cancer is a major cause of cancer-related mortality in the USA, and tobacco smoke is the major risk factor for this disease. However, many patients with lung cancer have never smoked (never smokers). Patients with lung cancer who have never smoked are more likely to have mutations in epidermal growth factor receptor (EGFR) tyrosine kinase and have better response to its inhibitors than do patients with tobacco-associated lung cancer. Furthermore, the prevalences of mutations in KRAS and P53 differ for patients with lung cancer who have never smoked and those with tobacco-associated lung cancer. Genetic mutations seem to be more common in patients with tobacco-associated lung cancer than in never smokers. Current evidence indicates that the two types of lung cancer are biologically distinct. Here, we review published studies of the molecular genetics of lung cancer in never smokers and identify the specific differences from tobacco-associated lung cancer.