Many biologically active peptides are localized in autonomic nerves of the orofacial region. Substance P and calcitonin gene-related peptide (CGRP) are released from capsaicin-sensitive afferents and are candidates as mediators of plasma protein extravasation and antidromic vasodilatation. Vasoactive intestinal polypeptide (VIP) and peptide with N- and C-terminal histidine (PHI) are released together with acetylcholine from parasympathetic nerves. VIP and PHI may be involved in both non-cholinergic vasodilatation and enhancement of cholinergic exocrine secretion (especially protein content). Neuropeptide Y (NPY) is coreleased with noradrenaline from perivascular sympathetic nerves. NPY exerts prejunctional inhibitory actions on noradrenaline release and may also mediate non-adrenergic sympathetic vasoconstriction. A variety of both anticholinergic and sympathoactive drugs influence not only the classical transmitters acetylcholine and noradrenaline but also the respective coexisting peptides VIP and NPY.