Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, with the greatest challenge for improving patient survival being the management of chemorefractory disease upon relapse. Epigenetic dysregulation has been correlated with more-aggressive malignancies and chemoresistance. In this issue of Cancer Discovery, Clozel and colleagues show the potential for low-dose DNA methyltransferase inhibitors as both a rational and an effective neoadjuvant approach for chemosensitization in DLBCL.