The eukaryote's mitochondrial network is perhaps the cell's most sophisticated and dynamic responsive sensing system. Integrating metabolic, oxygen, or danger signals with inputs from other organelles, as well as local and systemic signals, mitochondria have a profound impact on vascular function in both health and disease. This review highlights recently discovered aspects of mitochondrial function (oxygen sensing, inflammation, autophagy, and apoptosis) and discusses their role in diseases of both systemic and pulmonary vessels. We also emphasize the role of mitochondria as therapeutic targets for vascular disease. We highlight the intriguing similarities of mitochondria-driven molecular mechanisms in terms of both pathogenesis and therapies in very diverse diseases, such as atherosclerosis, pulmonary hypertension, and cancer, to support the foundation of a new field in medicine: mitochondrial medicine.