Non-small cell lung cancer (NSCLC) is a common, often fatal malignancy, and is most frequently diagnosed in the advanced stage. Systemic chemotherapy for advanced (Stage IIIB and IV), inoperable NSCLC has evolved over the course of the last few decades. Survival advantage was first noted with platinum chemotherapy, with ultimate development of platinum-containing doublet combinations, which have now become standard of care in the treatment of advanced NSCLC. Over the course of the last few years, multiple nonplatinum combinations have also been demonstrated to be efficacious, and the addition of bevacizumab to existing doublet regimens has improved outcomes in this population of patients. Maintenance regimens for advanced stage NSCLC are currently under extensive investigation. Clinical trials have also recently demonstrated increased efficacy for agents such as docetaxel and pemetrexed in the second line setting for refractory disease.