Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that impede the growth and/or survival of tumor cells. Depending on the physiological context, HDACi can induce apoptosis via two well-defined apoptotic pathways; the intrinsic/mitochondrial pathway and the death receptor (DR)/extrinsic pathway. A number of groups have demonstrated that overexpression of prosurvival Bcl-2 family members significantly reduces HDACi-mediated tumor cell death and therapeutic efficacy in preclinical models. In many cases, HDACi activate the intrinsic pathway via upregulation of a number of proapoptotic BH3-only Bcl-2 family genes including Bim, Bid, and Bmf. Additionally, HDACi can engage the extrinsic pathway through upregulation of DR expression, reductions in c-FLIP, and upregulation of ligands such as TRAIL. Overall, it appears that activation of the intrinsic apoptotic pathway is the predominant mechanism of HDACi-induced tumor cell death; however, the DR pathway may also be engaged, either to amplify the apoptotic signal through the intrinsic pathway or to directly induce cell death.