Small-cell lung cancer is a chemo-sensitive disease with a response rate ranging from 70 to 90% for first-line treatment; however, relapses are very common and as a result long-term survival is poor. Chemotherapy has demonstrated a benefit over the best supportive care, even in patients who have relapsed after initial treatment with a platinum-based regimen. Agents currently being used in salvage therapy include topotecan, cyclophosphamide, doxorubicin and vincristine regimen. In the last 5 years, several drugs have shown promise in initial evaluation; however, randomized phase III trials would be needed to answer this question. Our understanding of the biology of small-cell lung cancer has improved dramatically over the past few years and this has translated into the developments of new therapeutic targets for this disease. Agents affecting several targets, including bcl-2, matrix metalloproteinases, epidermal growth factors and angiogenesis, are being studied currently and have the potential to change the treatment paradigms of this otherwise fatal malignancy. This review focuses on the various current and future options, including cytoxic and targeted agents, for salvage therapy in patients with this disease.