After a certain degree of nihilism, chemotherapy has become the standard treatment for advanced and metastatic non-small cell lung cancer (NSCLC). The new chemotherapeutic drugs (vinorelbine, taxanes, gemcitabine, and irinotecan) and their associations with cisplatin have shown better response rates and survival in comparison with the standard regimens. This increase of survival is the main motive of the possible consideration of a second-line therapy in NSCLC patients. To this regard, the most promising drug may be docetaxel that, in a randomized trial comprising a best supportive care arm (BSC), documented a response rate of 7.6%, a longer median survival (31 weeks versus 21 of BSC), and a statistically better quality life. Other phase II studies obtained a response rate of 20% and 1-year survival of 40% using docetaxel. Also gemcitabine has shown interesting results in this setting, with a 19% response rate and a median and 1-year survival rate of 34 weeks and 45%, respectively. The activity of paclitaxel is not well defined because of conflicting results and deserves further investigations, while the efficacy of vinorelbine and irinotecan has been dismal. Large randomized trials comparing the treatment arm with best supportive care and a careful analysis of quality of life and cost-effectiveness will be needed to clarify the role of second-line therapy in advanced NSCLC.