Mitochondrial impairment and oxidative damage are intimately involved in the pathogenesis of neurodegenerative diseases. Which is the initiating event is probably irrelevant because each can set into motion a self-sustaining and amplifying feed-forward cycle between reactive oxygen species (ROS) generation and mitochondrial impairment. Recent approaches to the development of neuroprotective agents have therefore targeted mitochondria protection and/or reduction of oxidative stress. There are several hurdles in the quest for neuroprotective drugs. The difficulties include penetration of the blood-brain barrier and delivery of drugs to mitochondria. Here we describe a novel class of mitochondria-targeted peptides that can promote mitochondrial function, reduce mitochondrial ROS generation, inhibit mitochondrial permeability transition, and prevent apoptosis and necrosis. These peptides can readily penetrate the blood-brain barrier and have demonstrated efficacy in animal models of Parkinson's disease and amyotrophic lateral sclerosis.