Nerve terminals often contain morphologically distinct populations of large (75-110 nm) and small (45-55 nm) vesicles. The small vesicles are speculated to account for release of transmitter quanta as they accumulate at presynaptic membranes. Large vesicles can co-store neuropeptides and classical transmitters but their function in neurotransmission has been disputed because they do not appear to accumulate at chemical synapses. However, there is now evidence that the large vesicles play a role in neurotransmission or its modulation even though they may not be eminently involved in synaptic release. Thus, exocytosis occurs along the synapse-lacking membranes of peripheral noradrenergic varicosities. Large vesicles may continue to function in peptide release even after the classical transmitter has been depleted as demonstrated in the pig vas deferens. Three days of reserpine administration causes a parallel loss of noradrenaline and small vesicle contents but does not decrease enkephalin-like immunoreactivity or large vesicle electron density. In the central nervous system of the rat, where substance P and enkephalin have been localized to large vesicles, exocytosis occurs from several types of terminals. The large vesicles appear preferentially to release their contents at morphologically non-specialized sites even when characteristic synapses are present. Thus different mechanisms of transmitter and neuropeptide release may coexist. The nonsynaptic discharge may allow substances to diffuse over a wider distance whereas release into a synaptic cleft could restrict receptor interaction.