The antiproliferative effect induced by histone deactylase inhibitors (HDACi) is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug. The direct targeting of p21 is not feasible. An alternate approach could selectively target factors upstream or downstream of p21 that affect one or more specific aspects of p21 function. HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated (ATM) activity. KU60019, a specific ATM inhibitor, has shown to decrease the p21 protein levels in a concentration dependent manner. We explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor. KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase. Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor. We believe this strategy may offer a promising way to identify rational combinations for HDACi directed therapy, improving their activity in malignant disease.