Capsaicin-sensitive extrinsic afferent nerves have been demonstrated to release biologically active substances in the gastrointestinal (GI) tract. This fact may be useful for identifying sensory transmitter substances in isolated organ experiments. In the GI tract of animals neuropeptides like tachykinins and calcitonin gene-related peptide (CGRP) mediate specific excitatory and inhibitory effects of capsaicin; some evidence indicates a participation of purinergic mechanisms as well. The human gut (especially the circular musculature) is powerfully relaxed by capsaicin, and this effect seems to have a completely different transmitter background (nitric oxide (NO) and maybe VIP, neither of them of intrinsic neuronal origin). We propose that NO may be a sensory neurotransmitter. The "local efferent" (mediator-releasing) effect of extrinsic afferent neurons can also be demonstrated in vivo, both in animals and man. Yet, nearly normal motility of the small and large intestines (i.e., the most "autonomous" part of the GI tract) is maintained in animals with functionally inhibited capsaicin-sensitive nerves. The importance of this system in regulating GI movements may be exaggerated under pathopysiological conditions, first of all inflammation. The afferent function of capsaicin-sensitive nerves plays a role in sympathetic reflexes, such as the inhibition of GI motility after laparotomy or by peritoneal irritation.