Apoptosis is a cell suicide mechanism that enables organisms to control cell number and eliminate cells that threaten survival. The apoptotic cascade can be triggered through two major pathways. Extracellular signals such as members of the tumor necrosis factor (TNF) family can activate the receptor-mediated extrinsic pathway. Alternatively, stress signals such as DNA damage, hypoxia, and loss of survival signals may trigger the mitochondrial intrinsic pathway. In the latter, mitochondrial damage results in cytochrome c release and formation of the apoptosome, a multimeric protein complex containing Apaf-1, cytochrome c, and caspase-9. Once bound to the apoptosome, caspase-9 is activated, and subsequently triggers a cascade of effector caspase activation and proteolysis, leading to apoptotic cell death. Recent efforts have led to the identification of multiple factors that modulate apoptosome formation and function. Alterations in the expression and/or function of these factors may contribute to the pathogenesis of cancer and resistance of tumor cells to chemotherapy or radiation. In this review we discuss how disruption of normal apoptosome formation and function may lead or contribute to tumor development and progression.