Despite high response rates to first-line standard treatment, the great majority of patients with small cell lung cancer (SCLC) will relapse and succumb to their disease rather quickly. In the context of salvage therapy, symptom palliation and quality-of-life improvements, besides survival prolongation, are primary treatment endpoints. A variety of single-agent and multi-agent chemotherapy regimens have been tested with limited success in patients with recurrent SCLC. A number of combination regimens have demonstrated high response rates in second-line settings, but these can be considered only for patients with good performance status. Treatment outcome depends on many factors, including type of response to first-line therapy, treatment-free interval, and performance status. Currently, topotecan represents an effective, tolerable therapeutic option and is the only agent approved for this indication. The management of patients with recurrent disease remains an area of active research. This review provides an update of clinical research on second-line chemotherapy of SCLC and of recent results obtained with novel molecular targeted approaches in both first- and second-line therapy.