The hypothesis that substance P (SP) might be a transmitter of primary sensory neurons was first proposed by Lembeck in 1953. A large amount of evidence supporting this hypothesis has recently accumulated, particularly since the elucidation of the chemical structure of SP by Leeman and her colleagues in 1971, which made a number of new approaches possible (e.g. radioimmunoassay for SP, immunohistochemistry and electrophysiological tests of SP action on central and peripheral neurons). SP is concentrated in certain primary afferent terminals in the spinal cord, is released therefrom when the dorsal roots are electrically stimulated, and exerts a powerful excitant action on spinal neurons. It is therefore likely that SP produces excitatory postsynaptic potentials (EPSPs) in spinal neurons, although the characteristics of SP-mediated EPSPs, i.e. their time course, ionic mechanisms, etc., remain to be revealed. Recent electrophysiological and neurochemical studies on the prevertebral ganglia of the guinea-pig strongly suggest that SP is released from axon collaterals of visceral primary afferent neurons in the ganglia and serves as a transmitter that generates non-cholinergic slow EPSPs in principal cells. There is evidence that this SP-mediated synaptic transmission in the sympathetic ganglia is under the influence of enkephalinergic presynaptic inhibition. Some preliminary experiments on the interaction between SP and enkephalins in the spinal cord are described.