SCLC represents 13% of all lung cancer cases and is the most aggressive form of lung cancer with an overall 5-year survival less than 5%. The combination of cisplatin or carboplatin with etoposide remains the standard treatment for SCLC. Despite a good initial response to therapy, most SCLC patients suffer from the development of chemotherapy resistance and relapse. Second-line chemotherapy should then be applied, which however frequently results in only a low survival increase. To improve the outcome of SCLC, new drugs such as topotecan, irinotecan, amrubicin, paclitaxel or gemcitabin have recently been added to chemotherapeutic regimens. In combination with etoposide or platinum-based agents, some of these drugs could be able to offer a significant survival benefit. Moreover, recent progress in the understanding of SCLC biology has led to the identification of critical signaling pathways, which allowed the development of specific targeted therapies for the disease. A number of new molecules are currently under clinical evaluation in SCLC. These inhibitors target the proteasome, receptors tyrosine kinases, farnesyltransferase, Bcl-2, or angiogenic pathways. Some studies have demonstrated that these new strategies can be associated with chemotherapy and show positive results. This review summarizes recent clinical trials performed with new chemotherapeutic regimens and the current status of specific targeted approaches in SCLC patients.