The TMEM16A channel represents a key depolarizing mechanism in arterial smooth muscle and contractile pericytes, where it is activated by several endogenous contractile agonists. In this issue of Science Signaling, Mata-Daboin et al. demonstrate a previously unidentified role for TMEM16A in endothelial cells for acetylcholine-mediated vasorelaxation. Collectively, TMEM16A serves as a transducer of vasoactive stimuli to enable fine modulation of vessel tone.