Although elevated cholesterol and other recognised cardiovascular risk factors are important in the development of coronary artery disease (CAD) and heart attack, the susceptibility of humans to this fatal process is distinct from other animals. Mitochondrial dysfunction of cells in the arterial wall, particularly the endothelium, has been strongly implicated in the pathogenesis of CAD. In this manuscript, we review the established evidence and mechanisms in detail and explore the potential opportunities arising from analysing mitochondrial function in patient-derived cells such as endothelial colony-forming cells easily cultured from venous blood. We discuss how emerging technology and knowledge may allow us to measure mitochondrial dysfunction as a potential biomarker for diagnosis and risk management. We also discuss the "pros and cons" of animal models of atherosclerosis, and how patient-derived cell models may provide opportunities to develop novel therapies relevant for humans. Finally, we review several targets that potentially alleviate mitochondrial dysfunction working both via direct and indirect mechanisms and evaluate the effect of several classes of compounds in the cardiovascular context.