The importance of adenosine and ATP in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular homeostasis which may be used for management of hypertension and cardiovascular diseases. In response to ischemia and cardiovascular injury, ATP is broken down to release adenosine. The activity of adenosine is very short lived because it is rapidly taken up by myocardial and endothelial cells, erythrocytes (RBC), and also rapidly metabolized to oxypurine metabolites and other adenine nucleotides. Extra-cellular and intracellular ATP is broken down rapidly to ADP and AMP and finally to adenosine by 5’-nucleotidase. These metabolic events are known to occur in the myocardium, endothelium as well as in RBC. Exercise has been shown to increase metabolism of ATP in the RBC which may be an important mechanism for post exercise hypotension and cardiovascular protection. The post exercise effect was greater in hypertensive than in normotensive rats. The review summarizes current evidence in support of ATP metabolism in the RBC as potential systemic biomarker for cardiovascular protection and toxicities. It also discusses the opportunities, challenges and obstacles of exploiting ATP metabolism in RBC as target for drug development.