Abstract Cardiomyocytes are one of the most mitochondria-rich cell types in the body, with ∼30–40% of the cell volume being composed of mitochondria. Mitochondria are well established as the primary site of adenosine triphosphate (ATP) generation in a beating cardiomyocyte, generating up to 90% of its ATP. Mitochondria have many functions in the cell, which could contribute to susceptibility to and development of cardiovascular disease (CVD). Mitochondria are key players in cell metabolism, ATP production, reactive oxygen species (ROS) production, and cell death. Mitochondrial calcium (Ca2+) plays a critical role in many of these pathways, and thus the dynamics of mitochondrial Ca2+ are important in regulating mitochondrial processes. Alterations in these varied and in many cases interrelated functions play an important role in CVD. This review will focus on the interrelationship of mitochondrial energetics, Ca2+, and ROS and their roles in CVD. Recent insights into the regulation and dysregulation of these pathways have led to some novel therapeutic approaches.