The properties of BCL6 as a therapeutic target stem from its normal function in the humoral immune system, where it plays important roles enabling the survival of germinal center (GC) B-cells, which are the cells of origin of DLBCLs [1]. After T-cell–dependent antigen stimulation, B-cells migrate within lymphoid follicles and form GCs within which they undergo rapid proliferation while at the same time enduring somatic hyper mutation of their immunoglobulin loci [1]. BCL6 is required for GC B-cells to proliferate and tolerate the DNA damage that occurs as a byproduct of this process of immunoglobulin affinity maturation [1]. BCL6 mediates these effects by directly binding and repressing the replication checkpoint and DNA damage sensor encoding gene ATR as well as key checkpoint genes CHEK1, TP53, CDKN1A, CDKN2A and p14ARF [2–5]. GC B-cells that have generated high-affinity immunoglobulins are subsequently selected for terminal differentiation into antibody-producing plasma cells or memory B-cells through the actions of follicular T-helper and follicular dendritic cells. BCL6 also represses genes involved in terminal differentiation such as IRF4 and PRDM1 [1, 4], and so must be down regulated for exit from the GC reaction to occur. Hence, BCL6 not only enables but also maintains the GC B-cell phenotype. The checkpoint suppression properties of BCL6 are inherently pro-oncogenic and accordingly BCL6 is almost universally expressed in DLBCLs. DLBCLs can be sub classified according to gene expression profiles into various disease subtypes. Among these, the ABC (activated B-cell)-DLBCLs are generally considered to be derived from late GC B-cells in which BCL6 down regulation would normally occur [6]. Accordingly ABC-DLBCLs feature more frequent translocation of the BCL6 locus to heterologous promoters allowing for its constitutive expression. Although ABC-DLBCLs are often thought of as being BCL6-negative, this is likely due to the relatively low sensitivity of standard immunohistochemistry methods, and indeed, BCL6 protein can be detected in ABC-DLBCL cells when evaluated by more sensitive methods such as immunoblotting. The more prevalent GCB-type DLBCLs tend to express higher BCL6 protein levels even in the absence of translocations, reflecting their origin from GC B-cells [6]. Altogether, a majority of ABC-type and GCB-type DLBCLs require, and are hence “addicted” to, BCL6 to maintain their proliferation and survival, reflecting its function in normal GC B-cells and supporting the notion that BCL6 is a broadly relevant therapeutic target for DLBCLs [7–9].