Adenosine is an endogenous metabolite that has an anti-inflammatory effect across the vasculature. Extracellular adenosine activates 4 G-protein coupled receptors (A1, A3, A2A, and A2B) whose expression varies in different cells and tissues, including the vasculature and blood cells. Higher levels of adenosine are generated during stress, inflammation, and upon tissue damage. Some of the adenosine receptors (AR), such as the A2BAR, are further up-regulated following such stresses. This review discusses the role of adenosine and adenosine receptors in the development of atherosclerosis and some of the risk factors associated with this pathology. These include adenosine receptor-regulated changes in atherosclerosis, blood pressure, thrombosis, and myocardial infarction. Potential therapeutic applications are reviewed, as well as reasons for phenotypic differences occasionally observed between receptor knockout and pharmacological inhibition via drug administration.