Significance: Mitochondrial function is central to a wide range of biological processes in health and disease and there is considerable interest in developing small molecules that are taken up by mitochondria and act as either probes of mitochondrial function or therapeutics in vivo. Recent Advances: Various strategies have been used to target small molecules to mitochondria, particularly conjugation to lipophilic cations and peptides, and most of the work so far has been on mitochondria-targeted antioxidants and redox probes. In vivo studies will reveal whether there are differences in the types of bioactive functionalities that can be delivered using different carriers. Critical Issues: The outstanding challenge in the area is to discover how to combine the established selective delivery to mitochondria with the specific delivery to particular organs. Future Directions: These targeting methods will be used to direct many other bioactive molecules to mitochondria and many more wider applications other than just to antioxidants can be anticipated in the future. Antioxid. Redox Signal. 15, 3021–3038.