The acquisition of resistance to apoptosis, the cell’s intrinsic suicide program, is essential for cancers to arise and progress and is a major reason behind treatment failures. We show in this article that small molecule antagonists of the s-1 receptor inhibit tumor cell survival to reveal caspase-dependent apoptosis. s antagonist-mediated caspase activation and cell death are substantially attenuated by the prototypic s-1 agonists (+)-SKF10,047 and (+)-pentazocine. Although several normal cell types such as fibroblasts, epithelial cells, and even s receptor-rich neurons are resistant to the apoptotic effects of s antagonists, cells that can promote autocrine survival such as lens epithelial and microvascular endothelial cells are as susceptible as tumor cells. Cellular susceptibility appears to correlate with differences in s receptor coupling rather than levels of expression. In susceptible cells only, s antagonists evoke a rapid rise in cytosolic calcium that is inhibited by s-1 agonists. In at least some tumor cells, s antagonists cause calcium-dependent activation of phospholipase C and concomitant calcium-independent inhibition of phosphatidylinositol 3'-kinase pathway signaling. Systemic administration of s antagonists significantly inhibits the growth of evolving and established hormone-sensitive and hormone-insensitive mammary carcinoma xenografts, orthotopic prostate tumors, and p53-null lung carcinoma xenografts in immunocompromised mice in the absence of side effects. Release of a s receptor-mediated brake on apoptosis may offer a new approach to cancer treatment.