Prostaglandin-E2 receptors (EP1, EP2, EP3, P4) have emerged as very important biological targets with a variety of beneficial and deleterious functions during the development of a several peripheral and central nervous system diseases, via intracellular cAMP and Ca+2 signaling molecules. Several laboratories have been investigating the “yin-yang” roles of these receptors in physiology and neurodegenerative pathology and gliomas. This symposium will summarize the current developments in the field using genetic animal models, and small molecule modulators of these receptors indicating whether targeting these receptors will be a better strategy than traditional COX-2 inhibition, which led to adverse cardiotoxicity in human.