Pemetrexed is an antitumor agent traditionally used as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) as well as in combination with cisplatin for the treatment of chemonaïve patients with unresectable malignant pleural mesothelioma. Recently, pemetrexed has been approved in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology. Studies that support the development of this indication are detailed in this review. We performed a PubMed/Medline database search to identify relevant literature from 1998 until August 2008. Bibliographies from identified references were searched, as well as were abstracts from the most relevant congresses in lung cancer area (American Society of Clinical Oncology Congress, World Conferences of Lung Cancer). We detailed pemetrexed studies in the first-line setting of NSCLC treatment, in monotherapy, in combination with platinum and also, with other agents. Data regarding efficacy differences related to different histologic types were also analyzed.