Motility of the gastrointestinal tract is directly controlled by enteric inhibitory and excitatory motor neurons that innervate the layers of smooth muscle. Inhibitory motor neurons mediate receptive and accommodative relaxations and control the opening of sphincters, thus playing an important role in normal gut motility. Recent studies have demonstrated that nitric oxide (NO) is an important neurotransmitter released by inhibitory motor neurons in animal and human gut. Antagonists of nitric oxide synthase (NOS), the synthetic enzyme for NO, reduce the effectiveness of transmission from inhibitory motor neurons. Exogenous NO mimics inhibitory nerve activation, and a variety of compounds that affect the availability of endogenously produced NO modulate relaxations of gastrointestinal smooth muscle. It is clear, however, that NO is unlikely to be the only transmitter released by enteric inhibitory motor neurons: several other substances such as vasoactive intestinal polypeptide (VIP), or related peptides, and adenosine triphosphate (ATP) are also likely to contribute to nerve-mediated inhibition. The identification of NO as a major inhibitory neurotransmitter to gastrointestinal smooth muscle fills an important gap in our understanding of the physiological control of motility and opens up a wide range of new experimental possibilities. It may eventually lead to the development of new drugs for motility disorders. It should be noted, however, that NO is important in the brain, in cardiovascular control, in blood cell function and in many other organ systems, suggesting that it may be difficult to achieve specific pharmacological intervention targeted on inhibitory neurotransmission in the gut, without undesirable side effects.