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Stage III non-small-cell lung cancer (NSCLC) presents a major therapeutic problem for the radiation oncologist who treats patients outside of clinical trials. It is a heterogeneous disease with great variation of the clinical extent, and the optimal therapeutic decision must be based on various parameters: the most important unfavorable characteristics are represented by a low Karnofsky performance status, weight loss > 5%, locally too advanced disease (e.g. T4, positive pleural effusion), intensive symptomatology, and distant metastases. The presence of these factors advocates the use of short hypofractionated radiotherapy (RT) schemes of one or two fractions (e.g., 1 × 10 Gy, 2 × 8.5 Gy), which results in fast and effective palliation. Radical treatment must be given to patients without the above-mentioned unfavorable characteristics. Results from randomized clinical trials support the use of high RT doses, preferably hyperfractionated/ accelerated. The CHART schedule could be used in case of squamous-cell histology. Elderly patients could be treated by the standard scheme of 30 × 2 Gy (or equivalent). Chemotherapy reduces the risk of (other than brain) distant metastases and improves the median survival time, especially for patients with non-squamous-cell NSCLC. Platinum-based chemotherapy is usually administered in conjunction with RT as inductive and/or concurrent. Patients of stage IV are probably candidates for chemotherapy in case of good performance status and for a short-term radiotherapy if local symptoms are predominant.