The apoptotic pathway plays a critical role in facilitating tumor cell death. But there are mechanisms that enable cancer cells to suppress apoptosis, leading to treatment resistance and decreased tumor cell death. One mechanism is overexpression of inhibitors of apoptosis proteins (IAPs) that block the activation of critical caspases leading to apoptosis. This video explores how naturally occurring SMAC (second mitochondria derived activator of caspases) and therapeutic small molecule SMAC mimetics overcome IAP suppression of apoptosis, reestablishing both caspase activity and apoptotic tumor cell death.