The past decade has seen significant breakthroughs in our knowledge of the tumor biology of non-small cell lung cancer (NSCLC). Signaling pathways that are vital for tumor growth have been identified and have been effectively targeted for pharmacologic intervention. Furthermore, advances in imaging and treatment delivery have allowed radiation oncologists to deliver therapy more precisely to mobile tumors, while minimizing the dose to surrounding critical structures. This article summarizes the implications of these advances for the patient with unresectable locally advanced NSCLC and highlights ongoing work to improve clinical outcomes in this disease.