Recent studies suggest that primary changes in vascular resistance can cause sustained changes in arterial blood pressure. In this review, we summarize current knowledge about Cl⁻ homeostasis in vascular smooth muscle cells. Within vascular smooth muscle cells, Cl⁻ is accumulated above the electrochemical equilibrium, causing Cl⁻ efflux, membrane depolarization, and increased contractile force when Cl⁻ channels are opened. At least two different transport mechanisms contribute to raise [Cl⁻] _i in vascular smooth muscle cells, anion exchange, and cation-chloride cotransport. Recent work suggests that TMEM16A-associated Ca²⁺-activated Cl⁻ currents mediate Cl⁻ efflux in vascular smooth muscle cells leading to vasoconstriction. Additional proteins associated with Cl⁻ flux in vascular smooth muscle are bestrophins, which modulate vasomotion, the volume-activated LRRC8, and the cystic fibrosis transmembrane conductance regulator (CFTR). Cl⁻ transporters and Cl⁻ channels in vascular smooth muscle cells (VSMCs) significantly contribute to the physiological regulation of vascular tone and arterial blood pressure.