Hydroperoxy and hydroxy 20- and 22-carbon polyunsaturated fatty acids are enzymatically produced by a 12-lipoxygenase enzyme in human platelets. Their potential efficacy at the plateletvascular smooth muscle cell interface was evaluated in animals. Nanomolar levels of the hydroxylated fatty acids specifically antagonize both the vasoactive effects of thromboxane and its platelet aggregating effect, in vitro. This occurs in part through direct interference of receptor coupling to thromboxane. These studies have been extended to in vivo measurements of blood flow and demonstrate complete inhibition of thromboxaneinduced changes in systemic, coronary and cerebral blood flow. The human platelet is capable of producing these metabolites at nanomolar levels which is within their EC50 range. Moreover, increasing the precursor fatty acid in the diet results in an increase in the platelet tone of the respective metabolite. The chemical synthesis of the more potent hydroperoxy analogs and their actions will be presented in the summary of present preclinical developments. These endogenously produced biologically active metabolites may be involved in cardiovascular homeostasis and in certain pathophysiological states. The most potent derivatives may be of therapeutic value in occlusive disease.