Less than 30% of malignant gliomas respond to adjuvant chemotherapy. Here, we asked whether alterations in the pS3 and RB pathways and the expression of six BCL-2 family proteins predicted acute cytotoxicity and clonogenic cell death induced by BCNU, vincristine, cytarabine, teniposide, doxorubicin, camptothecin or β-lapachone in 12 human malignant glioma cell lines. Neither wild-type p53 status, nor p53 protein accumulation, nor p21 or MDM-2 levels, nor differential expression of BCL-2 family proteins predicted drug sensitivity, except for an association of BAX with higher β-lapachone sensitivity in acute cytotoxicity assays. p16 protein expression was associated with high doubling time and chemoresistance. We conclude that some important molecular changes, which are involved in the development of gliomas and attributed a role in regulating vulnerability to apoptosis, may not determine the response to chemotherapy in these tumors.