In many cell types, position in the cell cycle appears to play a role in determining susceptibility to apoptosis (programmed cell death), and expression of various cyclins and activation of cyclin-dependent kinases (CDKs) have been shown to correlate with the onset of apoptosis in a number of experimental systems. To assess the role of CDK-mediated cell cycle events in apoptosis, we have expressed CDK dominant negative mutants in human HeLa cells. Dominant negative mutants of CDC2, CDK2, and CDK3 each suppressed apoptosis induced by both staurosporine and tumor necrosis factor alpha, whereas a dominant negative mutant of CDK5 was without effect. Like CDC2 and CDK2, CDK3 was shown to form a complex with cyclin A in vivo. CDK5 did not bind cyclin A to any detectable extent. Overexpression of wild type CDC2, CDK2, CDK3, or cyclin A (but not cyclin B) markedly elevated the incidence of apoptosis in BCL-2+ cells, which otherwise fail to respond to these agents. These results help identify cell cycle events that are also important for efficient apoptosis.