Non-small-cell lung cancer (NSCLC) accounts for approximately 80%-85% of all cases of lung cancer; for patients with stage III disease, it accounts for approximately 40% of all cases. The treatment for unresectable stage III NSCLC is the combination of platinum-based chemotherapy and thoracic radiation. In this article, new targeted agents under investigation for possible integration into the combined therapy are reviewed. One of the most promising strategies is the inhibition of the epidermal growth factor receptor (EGFR) pathway. Radiation activates EGFR signaling, leading to radio-resistance by inducing cell proliferation and enhanced DNA repair. Several preclinical models have shown synergistic activity when cetuximab was combined with radiation therapy. Some phase II trials have evaluated the safety and efficacy of synchronous cetuximab and radiation therapy with promising results. Gefitinib has a radiosensitizing effect on cell lines and has been investigated in combination with radiation therapy for unresectable stage III NSCLC. However, disappointing results were observed in the maintenance treatment with gefitinib after chemoradiation therapy. Erlotinib has been tested in a phase I trial with chemoradiation therapy. Radiation induces tumor death by damaging cell membranes, DNA, and microvascular endothelial cells, which in response increase proangiogenic growth factors. Antiangiogenic agents reduce vascular density but improve tumor oxygenation. Use of vascular endothelial growth factor receptor (VEGFR) inhibitors enhances the therapeutic efficacy of irradiation in human NSCLC by hindering the repair of sublethal radiation damage. Trials combining erlotinib and bevacizumab with thoracic radiation are ongoing. New strategies must be developed for the integration of this triple-combination treatment. As radiation therapy enhances HSP90 chaperone function, causing radio-resistant lung cancer cells, therapeutic agents that block this path are likely candidates for decreasing radio-resistance by suppressing HIF-1alpha and VEGF expression and thus inhibiting the survival and angiogenic potential of lung cancer cells. Aurora kinase inhibitors with radiation therapy seem to have an additive effect in preclinical models in NSCLC and mesothelioma.