Extensive-stage small-cell lung cancer (ES-SCLC) is one of the most lethal malignancies, with a median overall survival of only 8-10 months with first-line chemotherapy despite response rates of 60%-80%. In the second-line setting, the prognosis is even more limited, with only 20%-30% of patients having a response and a median survival measured in weeks to months. This article will review systemic chemotherapy in first- and second-line treatment of patients with ES-SCLC and discuss novel therapeutic agents, cytotoxic and "targeted," with an emphasis on recently completed clinical trials and ongoing investigations.