The elderly and patients with Performance Status (PS) of 2, constitute the so-called special patient population. The tolerability of chemotherapy in this population is globally worse, and treatment approaches should be different. Platinum-based combination chemotherapy is currently recommended as the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), but its role in special patient population is controversial. The best treatment for elderly patients with advanced NSCLC is still debated. In the first randomized study dedicated to elderly NSCLC patients, single-agent vinorelbine showed superiority over supportive care alone, both in terms of survival and quality of life. In a large randomized trial, gemcitabine plus vinorelbine failed to show any advantage over either agent alone. Subset analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with an acceptable increase in toxicity for elderly patients. However, the role of platin-based chemotherapy needs to be defined in prospective randomised trials. With the current evidence, single-agent chemotherapy with a third-generation drug (vinorelbine, gemcitabine, taxanes) should be the recommended option for non-selected elderly patients with advanced NSCLC. Also for PS2 patients there is no consensus on standard treatment. On the basis of current evidence, chemotherapy treatment appears justified for patients with advanced NSCLC and PS2. Single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options. Stronger evidence is expected from new clinical research specifically focused on PS2 patients. High priority should be given to the evaluation of tolerability and efficacy of platinum-based combinations and role of new targeted therapies.