Purpose: Bcl-2 family antiapoptotic proteins are elevated in many human malignancies and are attractive therapeutic targets. The purpose of this study was to measure antiapoptotic Bcl-2 family expression in highgrade glioma to investigate potential targets for molecular therapy. Methods: Gene expression was investigated by QPCR and Western blot in 37 primary high-grade glioma surgical specimens and 12 GBM cell lines. Targeted reduction of gene expression was performed in GBM cell lines using transfected siRNAs or plasmid-based shRNAs. Increased gene expression was achieved using plasmid-based cDNAs. Spontaneous, ABT-737 or cisplatin-induced apoptosis was measured by FACS analysis of annexin V-stained cells. Gene promoter function was analyzed by luciferase reporter assay. Results: We found Mcl-1 to be the highest expressed antiapoptotic Bcl-2 family member in the majority of malignant gliomas. This was functionally important as neutralization of Mcl-1 induced apoptosis and increased sensitivity to the BH3 mimetic ABT-737 or cisplatin treatment in GBM cells. Sequencing of the Mcl-1 promoter identified a novel functional single nucleotide polymorphism (SNP) in a previously uncharacterized consensus ETS transcription factor binding site. We identified the ETS domain transcription factor ELK4 as a key regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 expression. Importantly the presence of the SNP, which ablated ELK4 binding, while uncommon in gliomas, was associated with low Mcl-1 levels and greater susceptibility to apoptosis following chemotherapy treatment. Furthermore, downregulation of ELK4 by siRNA, resulting in loss of Mcl-1 expression, increased sensitivity to ABT-737 and cisplatin treatment. Conversely, ELK4 overexpression increased Mcl-1 levels and this was shown to be protective against higher concentrations of the chemotherapy agent cisplatin. Conclusions: These findings demonstrate ELK4 to be a critical regulator of Mcl-1 expression in GBM and highlight both ELK4 and Mcl-1 as molecular therapeutic targets in high-grade glioma.