Several new agents have been introduced in the palliative treatment of advanced and metastatic NSCLC in the recent years. In randomized trials, the new third-generation regimens showed comparable efficacy to each other, but a better response rate and time to progression combined with a remarkably improved tolerability compared to "classic schedules". In patients who are not suitable for platinum-based therapy, monotherapy could be an attractive opportunity, as shown in randomized trials. In second-line therapy, the novel antifolate Pemetrexed showed comparable activity to Docetaxel with significantly reduced toxicity. Among the new oral tyrosine kinase inhibitors, Erlotinib proved to be active in second- and third-line treatments, whereas in first-line treatment, no survival benefit has been observed to date.