BCL-2 family protein interactions regulate apoptosis, a critical process that maintains tissue homeostasis but can cause a host of human diseases when deregulated. Venetoclax is the first FDA-approved drug to reactivate apoptosis in cancer by selectively targeting an anti-apoptotic BCL-2 family member. The drug’s activity relies on an ‘inhibit the inhibitor’ mechanism, whereby blockade of a key surface groove on BCL-2 disables its capacity to neutralize pro-apoptotic effectors, such as BAX, a chief executioner protein of the apoptotic pathway. A series of physiologic and pharmacologic regulatory sites that mediate the activation or inhibition of BAX have recently been identified, providing blueprints for the development of alternative apoptosis modulators to block pathologic cell survival or avert unwanted cell death by drugging BAX directly.