Lung cancer is the leading cause of cancer-related deaths world-wide and small-cell lung cancer (SCLC) accounts for up to 25% of lung cancer deaths. There has been a considerable amount of research in the understanding of the depth of biology of SCLC and utilizing this knowledge to develop targeted approaches. The treatment of SCLC remains a challenge, despite remarkable initial efficacy to combination chemotherapy and radiation therapy. The response is usually short-lived and the prognosis of SCLC has not changed over the past few decades, necessitating the critical need for evaluating novel agents/therapies. Several signaling pathways have been found to be activated in SCLC tumor cells, forming a rationale for blocking some of the drugable targets. Molecular changes and biological markers have been identified but remain to be validated. Novel and targeted agents have been evaluated but without much success. Increasing understanding of the biology and potential clinical evaluation of biomarkers will pave the way for more effective treatments.