Pemetrexed (Alimta) possesses broad antitumor activity. It has been evaluated in non-small-cell lung cancer (NSCLC) as front-line chemotherapy in a comprehensive phase II evaluation. While various antifolates have been previously evaluated in clinical trials, drug development was stopped or delayed in light of their lack of efficacy or occurrence of life-threatening toxicities. While similar trends were observed with pemetrexed early in development, investigators instituted folic acid and vitamin B12 supplementation to minimize these toxicities without hampering drug efficacy. This article briefly summarizes the current evidence that supports the role of pemetrexed-based combinations in clinical trials for chemonaive patients with advanced NSCLC.