The BCL-2 family pro-survival proteins are regulators of the intrinsic apoptosis pathway. Many human cancers overexpress one or more of these pro-survival proteins, which allows them to evade cell death: a hallmark of cancer. Targeting specific pro-survival proteins using BH3-mimetic drugs is a promising new anti-cancer therapy, exemplified by the success of the BCL-2 inhibitor Venetoclax, now FDA-approved for patients with chemotherapy refractory chronic lymphocytic leukemia and acute myeloid leukaemia (AML). Many tumour types are dependent on another pro-survival protein, MCL-1, for survival, and new BH3-mimetic drugs targeting this protein have shown promising results in preclinical models of blood cancers. These MCL-1 inhibitors have now entered clinical trials for certain B cell lymphomas, AML, and multiple myeloma. Innate or acquired resistance of cancer cells to Venetoclax is emerging as an issue in the clinic, with some of the genetic factors involved now being uncovered. However, little has been done to predict potential resistance factors for MCL-1 inhibition. We are using whole genome CRISPR/Cas9 screens to identify genes that contribute to resistance of MYC-driven lymphoma cells to treatment with MCL-1 inhibitors. Understanding the factors involved in the resistance of cancer cells to BH3-mimetic drugs targeting MCL-1 will help guide the use of these drugs in the clinic, both as single agents and in combination with other anti-cancer therapies.