Dynamic protein–protein interactions between proapoptotic and pro-survival Bcl-2 family members regulate outer-mitochondrial membrane permeabilization and cytochrome c release, key events in the path to apoptosis. Their relative levels often dictate the fate of a cell following an apoptotic stimulus. However, in cancer cells, the pro-survival Bcl-2 family members are frequently upregulated, thereby creating a constitutive block to apoptosis and resulting in continued cell survival under conditions that normally result in cell death. Because many chemotherapeutics used to treat cancer also trigger apoptosis, this upregulation of pro-survival members also contributes to resistance to conventional cancer therapies. Strategies that inactivate pro-survival Bcl-2 family members therefore suggest a means by which this downstream block in apoptosis can be alleviated, resulting in the selective killing of malignant cells. Here, we outline the progress of three small-molecule Bcl-2 antagonists that have advanced into clinical evaluation.