Cardiovascular disease accounts for almost half of all deaths worldwide, and has now surpassed infectious disease as the leading cause of death and disability in developing countries. At present, therapies such as LDL-lowering statins and anti-hypertensive drugs have begun to bend the morality curve for coronary artery disease (CAD); yet, as we come to appreciate the more complex pathophysiological processes in the vessel wall, there is an opportunity to fine-tune therapies to more directly target mechanisms that drive CAD. MicroRNAs have been identified that control vascular cell homeostasis,1–3 lipoprotein metabolism45–9 and inflammatory cell function.10 Despite the importance of these miRNAs in driving atherosclerosis and vascular dysfunction, therapeutic modulation of miRNAs in a cell- and context-specific manner has been a challenge. In this review, we will summarize the emergence of microRNA-based therapies as an approach to treat CAD by specifically targeting the pathways leading to the disease. We will focus on the latest development of nanoparticles as a means to specifically target the vessel wall, and what the future of these nanomedicines may hold for the treatment of CAD.