Second-messenger systems play a major role in mediating neurotransmitter actions. In recent years our understanding of the organization and function of two prominent second-messenger systems has progressed rapidly--the adenylate cyclase and phosphoinositide systems. Guanosine triphosphate-binding proteins, which are especially abundant in brain, couple transmitter receptors to the key second-messenger generating enzymes in both of these systems. Whereas activation of adenylate cyclase produces a single intracellular messenger, cyclic AMP, stimulation of the phosphoinositide system generates at least two, inositol trisphosphate and diacylglycerol. Inositol trisphosphate mobilizes calcium from intracellular stores, and diacylglycerol, like cyclic adenosine monophosphate, activates a phosphorylating enzyme, protein kinase C. These second-messenger systems are particularly enriched in the brain where they modulate many aspects of synaptic transmission.