Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. Mitochondria produce large amounts of free radicals, and mitochondrial oxidative damage can contribute to a range of degenerative conditions including cardiovascular diseases (CVDs). Although the molecular mechanisms responsible for mitochondrion-mediated disease processes are not correctly understood, oxidative stress seems to play an important role. Consequently, the selective inhibition of mitochondrial oxidative damage is an obvious therapeutic strategy. This review considers the process of CVD from a mitochondrial perspective and provides a summary of the following areas: reactive oxygen species (ROS) production and its role in pathophysiological processes such as CVD, currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases, and recent developments in mitochondria-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane. These mitochondrion-targeted antioxidants have been developed by conjugating the lipophilic triphenylphosphonium cation to antioxidant moieties such as ubiquinol. These compounds pass easily through biological membranes and, due to their positive charge, they accumulate several-hundred-fold within mitochondria. In this way they protect against mitochondrial oxidative damage and show potential as a future therapy for CVDs.