The incidence of lung cancer in 2007 is estimated to be 213,380 with 160,390 deaths in the United States. It contributed to 31% of male and 26% of female cancer-related deaths and is the largest cause of cancer-related mortality in both men and women. Despite some advances in the treatment of advanced non-small cell lung cancer (NSCLC), the introduction of third-generation cytotoxic agents (vinorelbine, gemcitabine, docetaxel, irinotecan, and paclitaxel) has not achieved a breakthrough in the dismal prognosis of this disease. Several meta-analyses have proved the superiority of 2- drug chemotherapy and cisplatin-based chemotherapy, but no gold standard exists. This paper summarizes the clinical data of a new cytotoxic agent, pemetrexed, and its combination with platinums in the treatment of NSCLC. The addition of vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or an EGFR-targeted drug (cetuximab) to pemetrexed/platinum in NSCLC, and the role of pemetrexed/platinum in adjuvant chemotherapy for early-stage NSCLC were also discussed in this paper.