The process of atherothrombosis is known to involve endothelial pathology (first drug target), plaque formation (second drug target) and thrombosis (third drug target). However it has recently been postulated that, even before endothelial pathology occurs, the very first step in the process of atherothrombosis is dysfunction of the arterial glycocalyx that lies between the endothelial cells and the blood . So there are really four drug targets, and perhaps the arterial glycocalyx will become the most important for future early prevention of people at risk. We will review the data available on the relationship of glycocalyx dysfunction to risk factors for atherothrombosis and indicate the areas of research that are required to elucidate this important new subject. Up to the present time, hyperglycaemia and oxidised LDL have been identified as causing glycocalyx dysfunction, and we will seek publications on drugs that modify these effects. Attempts are being made to explore the possibility of drug-induced reversal of hyperglycaemia-induced glycocalyx dysfunction. Progress is, however, dependent on grants being made available for work with the essential large animal (pig) experimental model for testing glycocalyx function. Such grants have hitherto not been sufficiently forthcoming, and this needs to be brought urgently to the attention of the pharmaceutical industry.