The most accepted upfront treatment for patients with advanced stage NSCLC has been platinum based chemotherapy. Current standard practice for treatment of stage IV non-squamous NSCLC patients with cytotoxic chemotherapy has evolved over the past decade. In a sentinel study in 2005, Sandler and colleagues demonstrated that the addition of bevacizumab to platinum doublet chemotherapy (carboplatin/paclitaxel) followed by maintenance bevacizumab conferred a survival advantage when compared to platinum doublet chemotherapy alone (12.1 mos vs. 10. mos) in patients with stage IV non squamous, non-small cell lung cancer. Following this, the largest phase III study ever conducted in stage IV NSCLC randomized more than 1700 patients with stage IV lung cancer to either cisplatin/pemetrexed or cisplatin/gemcitabine. This study was the first to reveal an interaction between chemotherapy and histology,demonstrating a survival advantage for the subset of patients with non-squamous cell treated with cisplatin/pemetrexed when compared to those treated with cisplatin/gemcitabine (11.0 vs 10 mos, p<0.05. Building upon this, a recent study evaluating maintenance pemetrexed (continuing treatment after the four cycles of platinum doublet therapy) in non-squamous cell lung cancer demonstrated a significant survival advantage for patients receiving maintenance pemetrexed vs. placebo after four cycles of cisplatin/pemetrexed (13.9 mos vs. 11.0 mos, p<0.05). Based on these studies, a regimen of cisplatin or carboplatin with pemetrexed followed by maintenance single agent pemetrexed has become one of the most accepted frontline treatments for patients with stage IV non-squamous, non small cell carcinoma.