1 Human skin mast cells, unlike other human mast cells so far studied, released histamine in a concentration-related manner in response to substance P, vasoactive intestinal peptide (VIP) and somatostatin (1 yM to 30 yM). In contrast, eledoisin, physalaemin, neurokinin A, neurokinin B, calcitonin gene-related peptide (CGRP), neurotensin, bradykinin and Lys-bradykinin induced negligible histamine release. 2 The low histamine releasing activity of physalaemin, eledoisin, neurokinin A and neurokinin B relative to substance P suggests that the human skin mast cell activation site is distinct from the tachykinin NK-1, NK-2 or NK-3 receptors described in smooth muscle.3 The relative potencies of substance P and its fragments SP2 11, SP3 11, SP4_11 and SP1,4 in releasing histamine from human skin mast cells suggests that both the basic N-terminal amino acids and the lipophilic C-terminal portion of substance P are essential for activity. 4 Peptide-induced histamine release, like that induced by compound 48/80, morphine and poly-Llysine, is rapid, reaching completion in 10-20s, is largely independent of extracellular calcium but requires intact glycolysis and oxidative phosphorylation. The substance P analogue, [D-Pro4,D-Trp7'9 "0] SP411 (SPA), not only reduced substance Pinduced histamine release in a concentration-related manner but also inhibited that induced by VIP, somatostatin, compound 48/80, poly-L-lysine and morphine but not anti-IgE. 6 The similar characteristics of histamine release induced by substance P. VIP, somatostatin, compound 48/80, poly-L-lysine and morphine suggest that they share a common pathway of activationsecretion coupling distinct from that of IgE-dependent activation. Furthermore, the ability of human skin mast cells to respond to basic non-immunological stimuli including neuropeptides may reflect a specialised function for these cells.