Apoptosis contributes to cell death in common intensive care unit disorders such as traumatic brain injury and sepsis. Recent evidence suggests that this form of cell death is both clinically relevant and a potential therapeutic target in critical illness. Mitochondrial reactive oxygen species (ROS) have become a target for drug discovery in recent years since their production is characteristic of early stages of apoptosis. Among many antioxidant agents, stable nitroxide radicals targeted to mitochondria have attracted attention due to their ability to combine electron and free radical scavenging action with recycling capacities. Specific mechanisms of enhanced ROS generation in mitochondria and their translation into apoptotic signals are not well understood. This review focuses on several contemporary aspects of oxidative stress-mediated mitochondrial injury, particularly as they relate to oxidation of lipids and their specific signaling roles in apoptosis and phagocytosis of apoptotic cells.