Chemotherapy for non-small cell lung cancer (NSCLC) can prolong survival and improve quality of life, but the majority of advanced stage patients succumb to disease within 2 years, meaning that there is room for improvement. The standard chemotherapy for NSCLC involves one of a number of chemotherapy doublets that have been shown to improve survival when compared with single agents or best supportive care. These doublets are generally comparable in terms of efficacy, differing primarily in their toxicity profiles. However, encouraging new options may be approaching, including therapies targeted to specific patient subpopulations, and the use of combinations of current and new drugs to produce synergistic effects. Targeted therapies include the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, EGFR monoclonal antibody cetuximab, and vascular endothelial growth factor (VEGF) inhibitors such as sorafenib, a small molecule TKI, and bevacizumab, a recombinant monoclonal VEGF antibody. Most attempts to combine EGFR-targeted therapies with standard chemotherapy in NSCLC have produced poor results, possibly as a result of antagonism between EGFR TKIs and chemotherapy. Positive results with bevacizumab suggest that VEGF-rather than EGFR-targeted therapies may produce better results when combined with chemotherapy. Other new drugs being tested include enzastaurin, an oral serine threonine kinase inhibitor; vinflunine, a vinca alkaloid; dihydrofolate reductase inhibitors; and thymidylate synthase inhibitors. Combinations of therapies, especially those acting via different mechanisms, hold promise for improvements in survival, but careful testing is required to determine optimum combinations of available drugs and where new drugs fit into the armamentarium.