It is now recognized that oxidative injury and mitochondrial dysfunction are responsible for many clinical disorders with unmet needs, including ischemia-reperfusion injury, neurodegeneration, and diabetes. Mitochondrial dysfunction can lead to cell death by apoptosis or necrosis. As mitochondria are the major source of intracellular reactive oxygen species (ROS), and mitochondria are also the primary target for ROS, the ideal drug therapy needs to be targeted to mitochondria. A number of approaches have been used for targeted delivery of therapeutic agents to mitochondria. This review will focus on a novel class of cell-permeable small peptides (Szeto-Schiller peptides) that selectively partition to the inner mitochondrial membrane and possess intrinsic mitoprotective properties. Studies with isolated mitochondrial preparations and cell cultures show that these SS peptides can scavenge ROS, reduce mitochondrial ROS production, and inhibit mitochondrial permeability transition. They are very potent in preventing apoptosis and necrosis induced by oxidative stress or inhibition of the mitochondrial electron transport chain. These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis, and they are remarkably free of toxicity. The pharmacology of the SS peptides in models of ischemia-reperfusion will be the focus of this review.