Over the past 100 years, our understanding of the pathogenesis of lung cancer has advanced impressively. Environmental carcinogens and a gene locus determining susceptibility have been identified. The pathology of lung cancer has been classified into categories with major clinical implications. The cellular and molecular genetic changes underlying lung cancer have become better understood over the past 25 years, but the stepwise progression of respiratory epithelium from normal to neoplastic is not yet well demarcated, limiting abilities to advance early detection and chemoprevention. The translation of improved understanding of dominant signal transduction pathways in lung cancer to rationally designed therapeutic strategies has had recent successes, demonstrating a proof of principle for targeted therapy in lung cancer. Improvement in overall patient outcomes has been stubbornly slow and will require concerted efforts.