Normal cells are up to ten times more resistant to histone deacetylase inhibitors (HDACis)-induced cell death compared with transformed cells. The molecular processes underlying this selectivity for cancer cells are still not well understood. Although a differential response to oxidative stress and capacity to repair damaged DNA have been described in some systems, these cannot fully account for the sensitivity of cancer cells to HDACis since the heterogeneity of cancer cells prompts differential sensitivities to reactive oxygen species and generates a panoply of defective DNA repair mechanisms within given histologies, cancer cell lines and tumor xenografts. It seems also unlikely that the influence of HDACis on cancer treatments reside primarily on gene transcription, since gene-expression profiling aimed at defining correlation with response to HDACis in cancer cells indicates that less than 5% to approximately 20% of transcribed genes are altered by HDACis treatment. Moreover, the altered genes vary from cell line to cell line and between different HDACis. Therefore, no consistent picture of a target(s) or pathway(s) modulated by HDACis has emerged. One consistent parameter that has however been observed in peripheral blood mononuclear cells of patients treated with HDACi is the accumulation of acetylated histones. Because one of the primary functions of histone acetylation is to increase chromatin accessibility, this article will explore the possibility that intrinsic molecular and structural characteristics of cancer cells provide a selective advantage for HDACis sensitivity.