Small-cell lung cancer (SCLC) is a disease with a poor prognosis and limited treatment options. Over the past 30 years, basic and clinical research have translated to little innovation in the treatment of this disease. The Study of Picoplatin Efficacy After Relapse (SPEAR) evaluated best supportive care with or without picoplatin for second-line SCLC treatment and failed to meet its primary end point of overall survival. As the largest second-line, randomized study in patients with SCLC, SPEAR provides an opportunity to critically examine the drug development model in this disease. In this Review, we discuss the current standard approach for the management of SCLC that progresses after first-line therapy, analyze the preliminary data that supported the evaluation of picoplatin in this setting, and critically evaluate the SPEAR trial design and results. Lastly, we present advances in the understanding of the molecular biology of SCLC that could potentially inform future clinical trials and hopefully lead to the successful development of molecular targeted agents for the treatment of this disease.