The presence of Ca(2+)-activated Cl(–) currents (I(Cl(Ca))) in vascular smooth muscle cells (VSMCs) is well established. ICl(Ca) are supposedly important for arterial contraction by linking changes in [Ca(2+)]i and membrane depolarization. Bestrophins and some members of the TMEM16 protein family were recently associated with I(Cl(Ca)). Two distinct I(Cl(Ca)) are characterized in VSMCs; the cGMP-dependent I(Cl(Ca)) dependent upon bestrophin expression and the ‘classical’ Ca(2+)-activated Cl(–) current, which is bestrophin-independent. Interestingly, TMEM16A is essential for both the cGMP-dependent and the classical I(Cl(Ca)). Furthermore, TMEM16A has a role in arterial contraction while bestrophins do not. TMEM16A’s role in the contractile response cannot be explained however only by a simple suppression of the depolarization by Cl(–) channels. It is suggested that TMEM16A expression modulates voltage-gated Ca(2+) influx in a voltage-independent manner and recent studies also demonstrate a complex role of TMEM16A in modulating other membrane proteins.