Important inroads have been made in the understanding and treatment of metastatic prostate cancer in recent years. However, the need for agents targeting novel pathways remains ever present. One such area with promise is through apoptosis or programmed cell death. Many perturbations within the apoptotic process have been associated with treatment resistance and progression in castration-resistant prostate cancer; thus, therapeutic potential exists with agents that can restore an effective apoptotic response to cellular stressors. This article focuses on agents in clinical development targeting apoptosis through the intrinsic and extrinsic pathways. We review the current status of agents that intervene at the Bcl2 checkpoints, humanized antibodies to death receptors, agents that target the inhibitors of apoptosis proteins, mimetics of small mitochondria-derived activator of caspases, and antisense therapies targeting cytoprotective chaperones. Although single-agent activity has been demonstrated with some of these agents, the clinical development path forward will see them coupled with standard hormonal therapy and chemotherapy. OGX-011 (custirsen), which inhibits expression of the cytoprotective chaperone protein clusterin, is the most mature of these agents and is being tested in combination with chemotherapy in phase III clinical trials for castration-resistant prostate cancer, and results are eagerly awaited.