Although the induction of apoptosis can be an effective strategy for anti-cancer chemotherapy, emergence of drug resistance to existing pro-apoptotic drugs is a serious concern. Understanding the molecular mechanisms involved in acquiring drug resistance is of great interest for driving the discovery of new agents designed to thwart the escape routes tumor cells use to circumvent current therapy. The oncoproteins of the Bcl-2 family are activated in many forms of cancer, including the well-characterized lymphoid tumors multiple myeloma (MM) and chronic lymphoblastic leukemia (CLL). Bcl-2 family members regulate apoptosis induced by many cytotoxic compounds through multiple protein-protein interactions. The pro-survival protein Mcl-1 interacts with Bcl-2 family oncoproteins, including Bim, to oppose cell death. Mcl-1 is highly expressed in hematopoietic stem cells and is regulated by growth factors. Blocking the effects of Mcl-1, particularly through the inhibition of its interactions with pro-apoptotic oncogenes of the Bcl-2 family, is a promising approach for dramatically slowing tumor initiation, progression, and apoptosis resistance, especially in MM, where Mcl-1 is essential for tumor survival. We have used ultra-high throughput screening (uHTS) coupled with hit optimization strategy to discover potent and selective inhibitors of the Mcl-1/Bim interaction, including a designated probe compound, ML311. This new small molecule (also known as EU-5346) will be a useful tool for studying lymphoid tumorigenesis and to demonstrate the potential for using this strategy in therapies intended to bypass apoptosis resistance pathways that are activated in drug-resistant tumors.