Approximately a third of patients with newly diagnosed non-small cell lung cancer (NSCLC) have locally or regionally advanced disease not amenable for surgical resection. Concurrent chemoradiation is the standard of therapy for patients with unresectable locally advanced NSCLC who have a good performance status and no significant weight loss. Prospective studies conducted over the past two decades have addressed several important questions regarding systemic therapy and thoracic radiation. They include the role of induction/consolidation chemotherapy, integration of newer chemotherapy agents with radiation and the impact of molecularly targeted agents. Improved radiation therapy techniques and precise targeting of the tumors have played a key role in this setting. Moreover, it has been shown that higher than conventional doses of thoracic radiation can be administered safely in combination with chemotherapy. This review will discuss these issues in detail and outline the strategies that need to be employed to improve the outcomes in patients with locally advanced NSCLC.