The focus of the Cheng laboratory is to elucidate the molecular mechanisms underlying cell death with the hope that the knowledge derived from our research can be translated into targeted therapeutics that triggers cell death in cancer. To meet the challenge, we employ an integrated approach involving molecular biology, cell biology, biochemistry, functional genomics, and mouse models to delineate three central cell death pathways: (1) the BAX/BAK-dependent, caspase-dependent pathway, (2) the BAX/BAK-dependent, caspase-independent pathway, and (3) the BAX/BAK-independent pathway. Our prior studies have helped delineate the mammalian core apoptotic pathway governed by the BCL-2 family proteins at the mitochondrion. We have molecularly, biochemically, and genetically delineated the core proapoptotic BCL-2 pathway, consisting of upstream BH3-only molecules (BH3s) and downstream BAX and BAK, which are activated by intrinsic death signals to execute mitochondrion-dependent apoptosis (Science 2010; 330:1390-3). Specifically, we have biochemically constructed the apoptotic machinery, identified gatekeepers of apoptosis, mapped apoptotic signaling networks, and modeled apoptosis in mice. Our studies presented an “interconnected hierarchical model”, which not only offers a common ground deciphering the complex interplays among BCL-2 subfamilies but also provides a molecular blueprint concerning the clinical application of BH3-mimetics, such as ABT-263 (a BCL-2/BCL-XL inhibitor), in killing cancer cells. Ongoing research aims at building a comprehensive roadmap of cell death and delineating aberrant survival/death signaling pathways in cancer. The overarching goal of our research is to develop cell death mechanism-based therapeutic strategies for cancer.