Aberrant hyperactivation of the cap-dependent protein synthesis apparatus has been documented in a wide range of solid tumors, including epithelial carcinomas, but causal linkage has only been established in breast carcinoma. In this report, we sought to determine if targeted disruption of deregulated cap-dependent translation abrogates tumorigenicity and enhances cell death in non-small cell lung cancer (NSCLC). NSCLC cell lines were stably transfected with either wild-type 4E-BP1 (HA-4E-BP1) or the dominant-active mutant 4E-BP1A37/A46 (HA-TTAA). Transfected NSCLC cells with enhanced translational repression showed pronounced cell death following treatment with gemcitabine. In addition, transfected HA-TTAA and HA-4E-BP1wt proteins suppressed growth in a cloning efficiency assay. NSCLC cells transduced with HA-TTAA also show decreased tumorigenicity in xenograft models. Xenograft tumors expressing HA-TTAA were significantly smaller than control tumors. This work shows that hyperactivation of the translational machinery is necessary for maintenance of the malignant phenotype in NSCLC, identifies the molecular strategy used to activate translation, and supports the development of lung cancer therapies that directly target the cap-dependent translation initiation complex.