Mitochondria are key regulators of cell life and death and play an important role in a wide range of diseases, including cancer, diabetes, cardiovascular disease, and the age-related neurodegenerative diseases. The unique structural and functional characteristics of mitochondria enable the selective targeting of drugs designed to modulate the function of this organelle for therapeutic gain. This forum discusses (a) potential new mitochondrial targets for therapeutic intervention, including components of the electron transport chain, the permeability transition, and the membrane dynamics protein mitofusin-2; (b) the role of mitochondria-targeted antioxidants including MitoQ and SS peptides in modulating reactive oxygen and chlorine species induced mitochondrial permeabilization and cell death; and (c) the potential use of SS peptides in ischemia and reperfusion tissue injury. In the future, mitochondrial drug-targeting strategies will be expected to open up avenues for manipulating mitochondrial functions and allow for selective protection or eradication of cells for therapeutic gain in a variety of diseases.