Neuropeptides are signaling molecules that interact with G-protein coupled receptors located both pre- and postsynaptically. Presynaptically, these receptors are localized in axons and terminals away from presynaptic specializations. Neuropeptides are stored in dense core vesicles that are distinct from the clear synaptic vesicles containing classic neurotransmitters such as glutamate and GABA. Because they require a stronger Ca(2+) signal than synaptic vesicles, dense core vesicles do not release neuropeptides with single action potentials but rather require high-frequency trains. Thus, neuropeptides only modulate strongly stimulated synapses, providing negative or positive feedback. Many neuropeptides have been found to inhibit glutamate release from presynaptic terminals, and the major mechanism is likely direct interaction of betagamma G-protein subunits with presynaptic proteins such as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor). The use of mouse genetic models and specific receptor antagonists are beginning to unravel the function of inhibitory neuropeptides. The opioid receptors kappa and mu, which are activated by endogenous opioid peptides such as dynorphin, enkephalin, and possibly the endomorphins, are important in modulating pain transmission. Dynorphin, nociceptin/orphanin FQ, and somatostatin and its related peptide cortistatin appear to play a role in modulation of learning and memory. Neuropeptide Y has important functions in ingestive behavior and also in entraining circadian rhythms. The existence of neuropeptides greatly expands the computational ability of the brain by providing additional levels of modulation.