Small cell lung cancer SCLC is an aggressive neuroendocrine subtype of lung cancer withhigh mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and DrugAdministration FDA-approved drugs to treat SCLC. We found that tricyclic antidepressantsand related molecules potently induce apoptosis in both chemonave and chemoresistant SCLC cells. The candidate drugs activate stress pathways and induce cell death in SCLC cells, atleast in part by disrupting autocrine survival signals involving neurotransmitters and theirG protein-coupled receptors. These experiments identify novel targeted strategies that can berapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.