Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic up-regulation of cyclin A–associated cyclin-dependent kinase 2 (cdk2) activity. In apoptotic cells, the C termini of the cdk inhibitors p21^Cip1/Waf1 and p27^Kip1 are truncated by specific cleavage. The enzyme involved in this cleavage is CPP32 and/or a CPP32-like caspase. After cleavage, p21^Cip1/Waf1 loses its nuclear localization sequence and exits the nucleus. Cleavage of p21^Cip1/Waf1 and p27^Kip1 results in a substantial reduction in their association with nuclear cyclin–cdk2 complexes, leading to a dramatic induction of cdk2 activity. Dominant-negative cdk2, as well as a mutant of p21^Cip1/Waf1 resistant to caspase cleavage, partially suppress apoptosis. These data suggest that cdk2 activation, through caspase-mediated cleavage of cdk inhibitors, may be instrumental in the execution of apoptosis following caspase activation.