Stroke is a leading cause of morbidity and mortality worldwide. It has been generally accepted that cerebrovascular remodeling during hypertension is one of the major contributors to the increased risk of stroke. Volume-regulated Cl- channel (VRCC) and calcium-activated Cl- channel (CaCC) are the two predominant types of Cl- channels in cerebral vascular smooth muscle cells (VSMC). Recent studies have demonstrated that ClC-3, a member of the voltage-gated ClC Cl- channel family, is the molecular candidate for VRCC in VSMC. And TMEM16A, a member of anoctamin family, is responsible for the native CaCC of VSMC in brain vessels. It has been shown that VRCC activity is enhanced but CaCC activity is decreased in cerebral VSMC, paralleling the severity of cerebrovascular remodeling induced by hypertension. In the present review, we will highlight the recent findings regarding the important roles of these two channels in VSMC proliferation, apoptosis, cell cycle regulation, vascular inflammation, reactive oxygen species production and cerebrovascular remodeling during the development of hypertension. In addition, the relationship between VRCC and clinical used agents for stroke prevention, such as statins, will be discussed. These findings suggest that Cl- channels may be potential new targets for the prevention of stroke.