We investigated the role of endothelial nitric oxide synthase (eNOS), norepinephrine (NE), and neuropeptide Y (NPY) in cutaneous vasodilation in response to local skin warming. In a two part study, we used four treatment sites on the skin of the forearm for insertion of microdialysis fibers, and placement of local skin heaters and laser-Doppler probes. We allowed an hour and a half for needle trauma resolution. We recorded 10 min of baseline data, begin drug perfusion for 50 min to ensure full receptor antagonism (alpha, beta, Y1) and enzyme inhibition. In both parts of the study, the local warming protocol was such that local skin temperature was increased from 33 to 42 °C at 0.5 °C * 15 s-1. In Part 1 of our study, we used three sites for drug treatment 1) L-NAA (eNOS inhibition), 2) Yohimbine (YOH) and Propranolol (PRO) (alpha- and beta-receptor antagonism), 3) a combination site (L-NAA+YOH+PRO), 4) untreated site for control. Treatments resulted in a reduction of vasodilation (P < 0.05) that did not differ (P > 0.05) from each other. In study 2 the same test procedure was utilized, with four treatment sites: 1) L-NAA, 2) BIBP (antagonize Y1-receptors), 3) L-NAA+BIBP, 4) control site. Treated sites resulted in a reduction (P < 0.05) of the vasodilator response when compared to control sites; again treatments did not differ (P > 0.05) from each other. These data indicate that NE and NPY are working via eNOS in cutaneous vasodilator response to local skin warming.