Both intrinsic and acquired resistance to chemotherapeutic drugs are major obstacles in the treatment of non-small-cell lung cancer. Apart from classical drug resistance mechanisms, the failure of tumor cells to undergo apoptosis also plays an important role in drug resistance. Mutations and defects in the apoptotic pathway are, therefore, additional factors that determine drug resistance. The tumor suppressor gene p53, the retinoblastoma gene, and the bcl-2 family members are important factors in this pathway. Recently much attention has been drawn to different apoptotic pathways induced by naturally occurring death receptor ligands (such as tumor necrosis factor, Fas ligand, and tumor necrosis factor-related apoptosis-inducing ligand) or induced by drugs that affect the downstream pathway from the epidermal growth factor receptor. Insight regarding the proteins that determine sensitivity for chemotherapeutic drugs could provide new targets for cancer treatment, which may help to at least partly overcome drug resistance in non-small-cell lung cancer