Most lymphomas originate from B-cells at late stages of differentiation, the most common precursor being the germinal center B-cell. At the molecular level, B-cell lymphomas are characterized by specific genetic aberrations, and in the more aggressive subtypes they usually involve the MYC protooncogene. In fact, the MYC-activating t(8;14) translocation is the hallmark of Burkitt (BL) and a subset of adult diffuse large B-cell lymphomas (DLBCL). Neoplastic transformation by the Myc oncoprotein is based largely on its ability to drive cell proliferation; however, when hyperactivated, Myc can also induce apoptosis. Thus, in aggressive lymphomas MYC is frequently co-activated along with components of cell survival pathways. For example, in the so-called double-hit (DHL) and triple-hit (THL) lymphomas MYC translocations are accompanied by that of BCL2, the key antiapoptotic gene, alone (in DHL) or in combination with BCL6 (in THL). This makes DHL/THL extremely refractory to standard chemotherapy and underscores the need for new treatment strategies targeting or bypassing BCL2. While small-molecule inhibitors of BCL2 (venetoclax, etc) are emerging as standards of care, acquired resistance continues to be a barrier to successful treatment.