The recent identification of the nociceptin receptor-nociceptin system and the description of its role in nociceptive processing has produced numerous investigative studies. A fundamental part of this research is to understand the cellular signaling events (i.e. the building blocks) upon which the pharmacology of this intriguing system is based. As anticipated, nociceptin receptor activation inhibits the formation of cAMP formation via a pertussis toxin-sensitive G-protein. This indicates that nociceptin receptor couples to the G(i)/G(o) class of G-protein(s). However, there is now growing evidence for nociceptin activation of additional signaling pathways, including MAP kinase and phospholipase C/[Ca(2+)](i). These signaling events are discussed in this review.