The broadly distributed monoaminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) exerts its actions via 14 classes of receptor. With the exception of 5-HT3 receptors, which gate a cation-permeable ion channel, all 5-HT receptors are coupled to G proteins. The core features of transduction via 5-HT receptors are well established, but much still remains to be learned, in particular, with regard to native populations in the brain. In this article, we survey the current knowledge of cellular signaling at G-protein-coupled 5-HT receptors and focus on several novel (and surprising) insights that have emerged over the past few years. We also highlight several promising directions for future research that should improve the understanding of serotonin signaling and ultimately permit its therapeutic exploitation in the control of central nervous system disorders. In view of the diversity of transduction mechanisms engaged by 5-HT, much of this discussion is relevant to other classes of G-protein-coupled receptors.