Traditionally, the tone of bronchial smooth muscle is mediated through the balance of two autonomic nervous systems. The existence of a third non-adrenergic non-cholinergic (NANC) nervous system in the lung has been demonstrated in animals. In contrast to high density parasympathetic innervation of smooth muscle, no evidence of adrenergic nerves was found in human airways. Electrical field stimulation of tracheal strips in guinea-pig produced an initial contraction followed by a relaxation. The contraction was blocked by atropine but the relaxation was not inhibited by a beta-adrenergic blocking agent. Immunohistochemical studies have shown that vasoactive intestinal peptide (VIP)-like immunoreactive nerves are present in the central nervous system and in the peripheral neuronal system of mammals including the human respiratory tract. Autoradiographic and immunocytochemical studies have demonstrated a high density of VIP receptors in airway epithelium, submucosal glands, pulmonary vessels and smooth muscle, especially in large airways. Functional studies in humans have confirmed the regulating role of VIP principally in the large airway.