Small cell lung cancer (SCLC) accounts for 20% of all lung cancer cases and has a dismal five- year survival rate of less than 5%. Cisplatin-based combination chemotherapy (along with radiation) is the cornerstone of SCLC therapy. Initially, cisplatin shows excellent results causing remission in 60-80% of the SCLC patients but within a year the tumor inevitably relapses and this relapsed tumor is resistant to cisplatin and radiation. A subset of SCLC tumors does not respond to cisplatin from the outset. These patients are said to have platinum-refractory SCLC tumors. Patients with platinum resistant or refractory disease have very limited therapeutic options, as the only standard chemotherapy with an FDA-approved drug, camptothecin (and its derivations), has an objective response rate of approximately 3% and little or no survival benefit. Such sobering statistics define the arena where there is an urgent need for agents which enhance the pro-apoptotic activity of camptothecin in human SCLC. The present study tests the ability of capsaicin to sensitize human SCLC cells to the pro-apoptotic effects of camptothecin. Caspase-3 activity assays reveal that the combination of camptothecin and capsaicin displayed greater apoptotic activity than the drugs used alone. We verified these results using a second apoptosis assay, namely the Cell Death ELISA and obtained similar results. Chou-Talalay isobologram analysis showed the interaction between camptothecin and capsaicin is synergistic. Chicken chorioallantoic membrane (CAM) assays confirmed the combinatorial apoptotic effects of capsaicin and camptothecin in human SCLC. The co-operative effects of capsaicin and camptothecin were also confirmed in human SCLCs xenografted on athymic mice. The combinatorial growth-suppressive activity of camptothecin (in SCLCs) were mediated by elevation of intracellular calcium and the calpain pathway. Our findings pave the way foster the hope of novel combination drug regimens for the treatment of human small cell lung cancer.