Abstract In previous reports, we have shown in SH-SY5 cells that olomoucine and roscovitine, two inhibitory drugs of cyclin-dependent kinases, caused apoptosis independent of the extrinsic pathway. In this experimental paradigm, apoptosis was refractory to the protective effects of either Bcl-2 or Bcl-XL overexpression. We are now reporting that the failure of Bcl-XL to prevent dell death was consistent with no effect on the kinetics of caspase activation and cytochrome c release. To further characterize this issue, we have discarded a direct effect of either olomoucine or roscovitine on mitochondrial permeability transition. Moreover, we have evidence that an intrinsic pathway took place in SH-SY5Y cells by showing the mitochondrial translocation of a GFP-Bax construct on transfection and treatment with cyclin-dependent kinase inhibitory drugs. Finally, we tested the effect of olomoucine and roscovitine on wild-type, bax−/−, bak−/−, and double bax−/−bak−/− mouse embryonic fibroblasts (MEF). In wild-type MEFs, both drugs induced cell death by apoptosis in a dose-dependent manner. In bax−/−, bak−/−, and, particularly, double bax−/−bak−/− MEFs, we observed the inhibition of apoptosis. In conclusion, olomoucine and roscovitine caused apoptosis through an intrinsic pathway, with Bax and Bak proteins being involved. [Mol Cancer Ther 2008;7(12):3800–6]