The vascular neuromuscular junction is described and the terms neuromodulation and cotransmission defined. Two main types of interaction between peptide and nonpeptide neurotransmitter substances during the local control of blood flow are distinguished. The first concerns the interacting roles of peptides and nonpeptides that coexist in, and are released from, perivascular nerve varicosities. Examples include the interactions of neuropeptide Y (NPY) with noradrenaline (NA) and adenosine 5'-triphosphate (ATP) released from some sympathetic nerves; vasoactive intestinal polypeptide (VIP) with acetylcholine (ACh) released from some parasympathetic nerves; and NPY and 5-hydroxytryptamine (5-HT) released from intracardiac neurones supplying coronary vessels. Possible interactions of substance P (SP) and calcitonin gene-related peptide (CGRP) with ATP released from some primary afferent sensory nerves are also considered. The second type of interaction concerns vascular neurotransmitters and locally released agents such as histamine, prostanoids, and bradykinin. Finally, a hypothesis is put forward in which it is suggested that peptides and nonpeptides released from endothelial cells during hypoxia lead to protective vasodilatation via receptors on the endothelium, while these substances released from perivascular nerves during different physiological circumstances usually constrict the blood vessel via receptors on the smooth muscle cells.