Small-cell lung cancer accounts for up to one-fifth of all lung cancers diagnosed. While the response rates to chemotherapy are high, ultimately the majority of patients will relapse and die from their disease. Long-term outcomes are poor. A number of new agents and novel strategies for the treatment of small-cell lung cancer are under evaluation, and this review outlines the current most promising agents and pivotal trials. Oblimersen, an antisense oligonuclide to the oncogene bcl-2, has been safely combined with chemotherapy. The proteosome inhibitor bortezomib has not demonstrated single-agent activity in phase II trials but is now being evaluated with proapoptotic triggers. A number of anti-angiogenic strategies have been evaluated in small-cell lung cancer. The vascular endothelial growth factor (VEGF) antibody bevacizumab and a number of VEGF receptor tyrosine kinase inhibitors are in the early phases of clinical trials. Results from trials have not demonstrated any survival advantage with the addition of matrix metalloproteinase inhibitors. A phase III trial has reported improvements in median survival with the addition of thalidomide to chemotherapy, but toxicity has been problematic. Immunotherapy with p53 vaccines and BEC2 antibodies have shown some promise and require further evaluation to determine whether humoral responses can predict for response. Trials with the immunoconjugate BB-10901 and temirolimus are ongoing.