Bcl-2 (B-cell lymphoma 2) protein functions as a potent inhibitor of apoptosis. Bcl-2 is highly expressed in many types of cancers. Therefore, Bcl-2 is a major target for developing anti-cancer drugs. Bcl-2 contains a BH3 binding domain which enables it to interact and neutralize other pro-apoptotic Bcl-2 family members resulting in inhibition of apoptosis. ABT-199 (Venclexta®) is a BH3 mimetic drug, approved by the FDA for treatment of CLL (Chronic Lymphocytic Leukemia) patients. ABT-199 acts by binding to Bcl-2 and neutralizing its anti-apoptotic effect, leading to death of the treated cancer cells. ARTS is a pro-apoptotic protein that promotes apoptosis by binding and degrading Bcl-2 through Ubiquitin-Proteasome-System (UPS). ARTS brings Bcl-2 into close proximity with X-linked inhibitor of apoptosis protein (XIAP). XIAP acts as an E3 ligase to ubiquitylate and degrade Bcl-2. Our lab has identified several ARTS-mimetic (AM) small molecules which bind XIAP and promote the degradation of both Bcl-2 and XIAP itself. This leads to killing of cancer cells. We have found that ABT-199 induces upregulation of Bcl-2 and MCL-1 levels in several cancer cell lines. Significantly, the combination of ABT-199 with Bx (an AM) reduces both Bcl-2 and MCL-1 expression. This culminates in a substantial increase in ABT-199 induced cell death. We show that Bx increases the direct binding of ARTS to XIAP which can activate the E3-ligase function of XIAP on Bcl-2. We hypothesize that Bx enhances the effect of ABT-199 on cancer cells by further degradation of Bcl-2 and XIAP, which amplifies the apoptotic outcome. Increased expression of MCL-1 is the potential cause of resistance to Bcl-2 inhibition by ABT-199. Our results provide an alternative and complementary approach to treatment of cancers that developed resistance to BH3 mimetics.