Overexpression of proto-oncogene products through mutation or translocation of BCL6, BCL2, REL, or c-MYC, constitutive activation of canonical and/or non-canonical nuclear factor kappa B (NF-κB) pathways through genetic lesions and mutations in TNFAIP3, CARD11, CD79A/B, MyD88 or TRAF2 and TRAF3 genes, respectively [15–18, 25–27], and/or epigenetic reprogramming, triggered by mutations in genes such as TET1, MLL2, EZH2, MEF2B, EP300 and CREBBP [15–17, 19, 20, 28–30], account for some of the most frequent cancer driver events in DLBCL [2]. The gene discussed is KMT2D; the disease is diffuse large B-cell lymphoma.