Pemetrexed is a novel multi-targeted antifolate that is used in the treatment of both malignant pleural mesothelioma and non-small-cell lung cancer (NSCLC). Lung cancer is the most common cancer in the world and NSCLC represents approximately 80% of all lung cancers. Pemetrexed is the first NSCLC drug for which 'treatment-by-histology' has been determined. This refers to the greater efficacy of pemetrexed in patients with advanced NSCLC other than of predominantly squamous-cell histology. The advent of treatment-by-histology represents a significant step forward in the treatment of lung cancer, allowing physicians to tailor therapies to the individual patient. Ongoing trials aim to establish the place of pemetrexed in maintenance, in combination with other 'targeted agents', in adjuvant therapy in early NSCLC and in concurrent radio/chemotherapy.