Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide, and the advances in second and third line treatment have led to prognostic improvements in the latest years. Besides the two cytotoxic agents, docetaxel and pemetrexed, approved in NSCLC second line treatment, a new class of drugs against specific molecular targets seems to be an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in association, and new combinations of third-generation chemotherapeutic agents.