Several peptides originally described as neurotransmitters or gut hormones have recently been shown to modulate the immune response. Three of these peptides, vasoactive intestinal peptide, substance P, and somatostatin, regulate the function of immune effector cells in gut-associated lymphoid tissue. Vasoactive intestinal peptide modulates lymphocyte migration and natural killer cell activity by a cyclic adenosine monophosphate (cAMP)-dependent mechanism, whereas substance P induces mediator release by a cAMP-independent mechanism. Somatostatin antagonizes the effects of both vasoactive intestinal peptide and substance P by a mechanism that appears to involve inhibitory guanine nucleotide binding proteins. Neuropeptide regulation of immune cells in gut-associated lymphoid tissue may thus play an important role in gastrointestinal physiology.