In the last three decades, treatment for small cell lung cancer has improved with advances in chemotherapy and radiotherapy. Almost all patients respond initially to standard chemotherapy, and some patients with limited stage disease are cured with the combination of chemotherapy and thoracic irradiation. Nonetheless, the majority of patients will experience lethal relapse from chemotherapy-resistant micrometastatic disease, and this has resulted in poor long-term survival for most patients. Addressing the problem of relapse requires unique approaches to eliminating minimal residual disease. This review will focus on the detection of minimal residual disease as well as strategies with which to treat it, including matrix metalloproteinase inhibitors, tyrosine kinase inhibitors, and vaccine therapy.