The management of advanced non-small cell lung cancer (NSCLC) has progressed over the last 3 decades. Advances in chemotherapeutic drugs and the use of multi-drug combinations, targeted agents and new management strategies have provided modest survival benefits. However, improving quality of life is equally important, and involves a therapeutic strategy that considers the optimal balance between treatment activity (survival; symptom control) and treatment burden (side effects; duration of hospital stay). There remains room for improvement of therapies today, given that 1-year survival is approximately 35%. The option of adding another cytotoxic agent to a platinum-based doublet does not appear to improve survival but increases toxicity. With the advent of targeted drugs, there is much interest in adding a biological agent such as bevacizumab to the current standard. Another strategy of interest is the use of maintenance treatment with a well-tolerated cytotoxic agent such as gemcitabine after first-line therapy. This has been shown to improve progression-free survival compared with best supportive care alone. Ten years ago, few patients with advanced NSCLC were candidates for second-line treatment for progressive or relapsed disease. However, as response rates and toxicity profiles with first-line therapies improved, relapse therapy has become more important. Several single agent chemotherapies have been evaluated in the second-line setting, including the anti-metabolite pemetrexed, which demonstrates comparable survival outcomes to that of the historical standard docetaxel, but a much better toxicity profile. The targeted therapy erlotinib is also being investigated in this setting. Further studies are required to establish the role of newer agents in the management of advanced NSCLC.