Apoptotic cell death regulated by the Bcl-2 family of proteins plays a critical role in the development and functioning of our immune system. A myriad of interactions between the pro-survival and pro-apoptotic members of this family of proteins dictate whether a cell lives or dies. Owing to this complexity, establishing the mechanisms by which the family members interact to control the intrinsic apoptotic pathway has proven challenging. Mechanistic insights have primarily been gleaned from in vitro studies because genetic approaches in mammals that produce unambiguous data are difficult to design. Here, I will describe a novel mouse model that provides a complete physiological readout of the interaction between Bcl-xL and Bak. These mice carry a germline point mutation in the BH3 domain of Bak, which reduces its affinity for Bcl-xL via loss of a single hydrogen bond. In vitro, cells derived from these mice were significantly more sensitive to various apoptotic stimuli, including chemotherapeutics. In vivo, loss of Bcl-xL binding to Bak led to significant defects in T cell and blood platelet survival. This model provides the first definitive in vivo evidence that Bcl-2 pro-survival proteins maintain cellular viability by interacting with and inhibiting the executioner of apoptosis, Bak.