Small cell lung cancer (SCLC) represents 13% of all lung cancer cases diagnosed in the United States. Although a chemotherapy and radiation-sensitive disease, SCLC recurs rapidly with only 5% of patients surviving five years. This dismal prognosis likely is secondary to few improvements in its treatment, without significant changes in its standard of care over the last three decades. SCLC has a unique biology with specific molecular and cellular changes, which are the subject of active investigation. Here, we summarize the alterations leading to the pathogenesis of SCLC: chromosomal changes; dysregulation of tumor suppressor genes, oncogenes, and signaling pathways; upregulation of receptor tyrosine kinases, growth factors and cellular markers; and the persistence of developmental pathways. Each of these represents potential targets for therapy and many biologic agents are being studied.