A cardiogenic hypertensive chemoreflex is elicited by serotonin administered experimentally in the dog. The reflex nearly doubles aortic pressure within 4-6 sec and is associated with powerful inotropic, chronotropic, and dromotropic responses. The afferent pathway is via intrathoracic vagal branches, whereas the efferent paths engage not only the vagal and sympathetic routes but also the phrenic nerve. The reflex can be abolished by vagotomy or with cyproheptadine, and can be attenuated by local anesthesia of the intertruncal space. Small chemoreceptors lying between the aorta and pulmonary artery are the source of the reflex, and they receive their blood supply from the proximal left coronary artery. Human counterparts of the reflex may include new hypertension during angina pectoris or acute myocardial infarction, new postoperative hypertension after coronary bypass grafting, and hypertensive patients with carcinoid syndrome. Many unresolved problems include the precise mechanism of chemoreception, whether the chemoreflex has any tonic influence, and mechanisms of integration of the reflex with other events peripherally and centrally. Answers to these questions could be of great clinical value.