The BCL6 proto-oncogene encodes a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation, and survival. BCL6 suppresses p53 in GCB-cells and its constitutive expression can protect B-cell lines from apoptosis induced by DNA damage. BCL6-mediated expression may allow GCB-cells to sustain the low levels of physiological DNA breaks related to somatic mutation (SM) and immunoglobulin class switch recombination which physiologically occur in GCB-cells. Three types of genetic events occur in the BCL6 locus and involve invariably the 5' non-coding region and include translocations, deletions and SM actively targeted to the 5' untranslated region. These acquired mutations occur independently of translocations but may be involved in the deregulation of the gene and/or translocation mechanisms. The favorable prognostic value of high levels of BCL6 gene expression in NHL seems well-established. By contrast, the relevance of SM or translocation of the gene remains unclear. However, it is likely that non-Hodgkin's lymphomas (NHL) harboring the most frequent translocation involving BCL6, i.e. t(3;14), are characterized by a common cell of origin and similar oncogenic mechanisms. Several experiments and mouse models mimicking BCL6 translocation occurring in human lymphoma have demonstrated the oncogenic role of BCL6 and constitute a rational to consider BCL6 as a new therapeutic target in NHL. BCL6 blockade can be achieved by different strategies which include siRNA, interference by specific peptides or regulation of BCL6 acetylation by pharmacological agents such as SAHA or niacinamide and would be applicable to most type of B-cell NHL.