Prostaglandin (PG) E(2) produces a broad range of physiological and pharmacological actions in diverse tissues through specific receptors on plasma membranes for maintenance of local homeostasis in the body. PGE receptors are divided into four subtypes, EP1, EP2, EP3, and EP4, which have been identified and cloned. These EP receptors are members of the G-protein coupled receptor family. Among these subtypes, the EP3 receptor is unique in its ability to couple to multiple G proteins. EP3 receptor signals are primarily involved in inhibition of adenylyl cyclase via G(i) activation, and in Ca(2+)-mobilization through G(beta)(gamma) from G(i). Along with G(i) activation, the EP3 receptor can stimulate cAMP production via G(s) activation. Recent evidence indicates that the EP3 receptor can augment G(s)-coupled receptor-stimulated adenylyl cyclase activity, and can also be coupled to the G(13) protein, resulting in activation of the small G protein Rho followed by morphological changes in neuronal cells. This article focuses on recent studies on the novel pathways of EP3 receptor signaling.