Cell death is a normal facet of human physiology, ensuring tissue homeostasis by offsetting cell production with cell demise. Neoplasms arise in part because of defects in physiological cell death mechanisms, contributing to pathological cell expansion. Defects in normal cell death pathways also contribute to cancer progression by permitting progressively aberrant cell behaviors, while also desensitizing tumor cells to immune-mediated attack, radiation, and chemotherapy. Through basic research, much has been learned about the molecular mechanisms responsible for cell turnover and how tumors escape cell death. By exploiting this knowledge base, several innovative strategies for eradicating malignancies have materialized that are based on restoration of natural pathways for cell autodestruction. Some of these strategies have advanced into human clinical trials. Several of the current strategies based on targeting core components of the cell death machinery for cancer therapy are reviewed here, and a summary of progress toward clinical applications is provided.