The actions of drugs on the antrum and duodenum of the dog were analyzed by the use primarily of intra-arterial injections into the gastroepiploic artery while the electrical and contractile activity of these regions was recorded. Histamine (0.1 to 5 μg) usually caused excitation of second potentials (antrum) or fast spikes (duodenum), and contractions (both) and other effects similar to those produced by acetylcholine, though usually delayed in onset and more prolonged. Its effects were diminished or prevented by atropine, nicotine, and hexamethonium as well as by antihistaminics such as antazoline, cyproheptadine, and phenoxybenzamine. In the duodenum, histamine excitation was usually preceded by inhibition, and most antihistaminics also depressed responses to serotonin (5-HT), acetylcholine, or both. Low doses of serotonin (0.1 to 1 μg) most frequently caused excitation of the antrum and duodenum similar to that evoked by acetylcholine. This response was sometimes prolonged. These effects in the antrum were diminished or prevented by atropine, nicotine, methysergide, and bromolysergic acid (BOL), and less effectively antagonized by hexamethonium, morphine, and pronethalol. Phenoxybenzamine did not prevent excitation of the antrum by low doses of 5-HT, but tachyphylaxis following high doses of 5-HT (5 to 100 μg) or of phenyldiguanide (25 to 500 μg) did prevent such responses. Several of these agents also inhibited excitation of the duodenum induced by 5-HT and cross tachyphylaxis between 5-HT and phenyldiguanide was also observed. It was suggested that low doses of 5-HT, like phenyldiguanide, acted at a preganglionic site in the antrum and duodenum different from that at which histamine acts, presumably the non-medullated mucosal mechanoreceptors, and ultimately caused release of acetylcholine from postganglionic fibers. Phenyldiguanide in small doses (2 to 25 μg) acted like 5-HT to excite the antrum and duodenum. Analysis of its action with antagonists yielded results similar to those with 5-HT, and the occurrence of cross tachyphylaxis with 5-HT suggested a common site of action. Morphine (10 to 1000 μg) usually inhibited electrical and contractile activity in the antrum and stimulated these activities in the duodenum. The same results were obtained with intravenous injection (0.1 to 0.35 mg/kg). It. diminished responses to histamine, 5-HT, phenyldiguanide, and to a lesser extent, acetylcholine.