Small-cell lung cancer (SCLC) accounts for almost 15% of lung carcinomas. Chemotherapy is the cornerstone of treatment of patients with SCLC. In limited disease, median survival is about 12-20 months, with no more than 6%-12% of patients surviving beyond 5 years. In extensive disease, median survival is 7-12 months, with < 5% of patients living beyond 2 years and a 5-year survival rate of just 2%. Several therapeutic approaches have been used in an attempt to improve the outcome of SCLC. Among these, a better understanding of tumor biology and the subsequent development of novel therapeutic strategies have been identified as a possible approach for increasing the survival rate of patients with SCLC. Several targeted agents have been introduced into clinical trials in SCLC, and a few phase III studies, including matrix metalloproteinase inhibitors, thalidomide, and vaccines, have already produced definitive results. Currently, negative results are more commonly reported than positive ones. However, this first generation of clinical trials represents only the beginning of clinical research in this field. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. Nevertheless, clinical research in this field is still in progress considering that several new targeted agents, such as antiangiogenic agents and mammalian target of rapamycin inhibitors, offer a promise of improved outcomes. This review will focus on the reported results and the future development of the main novel biologic agents for the treatment of patients with SCLC.