Despite the high response rates to chemotherapy, small-cell lung cancer (SCLC) is among the most lethal malignancies. Long-term survival is anecdotal for patients with extensive disease; 5-years survival is < or =5% for those with limited disease. All patients with extensive disease and most patients with limited disease will experience disease progression and become candidates for second-line therapy. Although a number of agents have demonstrated antitumor activity in relapsed SCLC, including paclitaxel, docetaxel, etoposide, cisplatin, and carboplatin, topotecan is the only single agent currently approved in the United States for the treatment of recurrent disease. Topotecan is a novel topoisomerase I inhibitor with established antitumor activity in recurrent SCLC and has a predictable, noncumulative toxicity profile. Furthermore, topotecan has been shown to provide symptom improvement in this predominantly palliative setting. Evidence also suggests that topotecan readily penetrates the blood-brain barrier and might be active in the relatively large subset of SCLC patients who experience brain metastases. This article reviews the clinical utility of topotecan in recurrent SCLC, including its efficacy, tolerability, and quality-of-life effect, when used as monotherapy and in novel combination regimens.