Despite advances in chemotherapy, the prognosis for advanced non-small-cell lung cancer (NSCLC) remains dismal. Increasing understanding of the biological processes responsible for lung carcinogenesis has led to development of new therapeutic strategies targeting this disease at a molecular level. This article examines the molecular events believed to lead to cellular changes in lung cancer, and how knowledge of these is used to develop new agents used individually or in combination with available cytotoxic drugs to improve survival. Finally, it explores how a deeper understanding of the embryonic signaling pathways responsible for airway epithelial repair and tumorogenesis, such as Hedgehog (Hh), Notch, and Wingless (Wnt), can lead to the development of newer and more specific therapies for lung cancer.