Mitochondria have been classically characterized as organelles with responsibility for cellular energy production in the form of ATP, but they are also the organelles through which apoptotic signaling occurs. Cell stress stimuli can result in outer membrane permeabilization, after which mitochondria release numerous proteins involved in apoptotic signaling, including cytochrome c, apoptosis-inducing factor, endonuclease G, Smac/DIABLO and Omi/HtrA2. Cell fate is determined by signaling through apoptotic proteins within the Bcl-2 (B-cell lymphoma 2) protein family, which converges on mitochondria. Many cancerous cells display abnormal levels of Bcl-2 protein family member expression that results in defective apoptotic signaling. Alterations in bioenergetic function also contribute to cancer as well as numerous other disorders. Recent evidence indicates that several pro-apoptotic proteins localized within mitochondria, as well as proteins within the Bcl-2 protein family, can influence mitochondrial bioenergetic function. This review focuses on the emerging roles of these proteins in the control of mitochondrial activity.