This review considers the possibility that histamine functions as a cellular messenger in the gastrointestinal tract. Any biological messenger must be produced, received, and responded to, and must have its actions quickly terminated. Histamine is no exception. Histamine synthesis from L-histidine occurs in enterochromaffin-like cells, mucosal mast cells, and nerves. Histamine release occurs through both antibody-dependent and antibody-independent mechanisms. Released histamine interacts with a variety of cellular targets (epithelial cells, smooth muscle cells, endothelial cells, neurons, and a variety of immunocompetent cells). Occupation of H1, H2, and H3 receptors, defined by pharmacological agents, is transduced by different intracellular messengers (Ca2+, cyclic nucleotides) into diverse effects such as secretion, contraction, or modulation of other secretagogues. The responses to histamine are terminated by at least three different mechanisms: metabolic transformation by the actions of methyltransferase and diamine oxidase, desensitization at the receptor level, and cellular uptake. In addition to its well-documented effects as a mediator of inflammatory processes, histamine may also function as a neuro- and immunoregulator. While a significant pathophysiological role for histamine has been realized since the earliest description of its effects, the availability of newer pharmacological agents has permitted a finer dissection of its "physiological" effects and raised the possibility of multiple roles for histamine.