The current prognosis for patients with extensive stage (ES) small-cell lung cancer (SCLC) remains poor, even though considerable improvements have been made in treatments for limited stage (LS) SCLC over the past several decades. Pemetrexed is an antimetabolite with an innovative mechanism of action. It demonstrates activity both as a single-agent and in combination regimens in patients with non-small-cell lung cancer (NSCLC) or malignant pleural mesothelioma. With an excellent antitumor activity, favorable tolerability profile, ease of administration and convenient schedule in NSCLC patients, pemetrexed is currently being investigated in a phase II trial for the first-line treatment of ES SCLC. Observations from this trial will help to define the future role of pemetrexed in SCLC.