Diffuse large B-cell lymphoma, the most common lymphoma subtype, is curable in the majority of patients. However, one of the greatest unmet needs in lymphoma treatment remains novel approaches to prevent relapsed or refractory disease. Genomic profiling has provided important prognostic information that is being used in the development of novel therapeutic strategies currently in clinical trials. It is clear, however, that epigenetic alterations provide an additional series of targets that can be pharmacologically modified and offer great potential to improving patient outcomes. Greater understanding of this area is providing important new insights that are now being explored in the clinical setting. Demethylating agents and drugs that disrupt histone modifiers are in early clinical trials with promising results, and other approaches targeting epigenetic pathways are in active preclinical and early clinical development.