Apoptotic cell death is classically regarded as immunologically silent. The mitochondrial or “intrinsic” apoptotic pathway is an evolutionarily conserved, BCL-2 family regulated, process that promotes the death and phagocytic clearance of stressed, damaged or infected cells. BAX and BAK-mediated mitochondrial membrane damage is essential for mitochondrial apoptosis, and is required for the downstream activation of apoptotic effector caspase activity. Consequently, the study of BAX/BAK regulation in cancer cells has resulted in the development of rationally designed BH3-mimetics compounds that trigger BAX/BAK to induce cancer cell death. However, research into the consequences of activating mitochondrial apoptosis in innate immune cells, such as macrophages, is less well studied. Using a range of targeted BH3-mimetic compounds, and other cancer chemotherapeutics, we have discovered the key pro-survival BCL-2 family members required to prevent spontaneous BAX/BAK apoptotic cell death in macrophages. Unexpectedly, we also observed that BAX/BAK signaling in macrophages triggers the activation of inflammasome-associated caspase, caspase-1, resulting in the activation and release of the pro-inflammatory cytokine, interleukin-1b (IL-1b). Using a panel of mice deficient in apoptotic signaling machinery, inflammasome sensor proteins or inflammatory caspases, we have defined a novel pathway by which BAX/BAK can cause inflammation via NLRP3 inflammasome activation. We believe this molecular pathway may underpin observations linking chemotherapeutic and cellular stress responses to inflammasome and IL-1b-driven inflammation.