Abstract: CLC-3 chloride （Cl-） channel，a member of an extended family of voltagegated CLC chloride channels and transporters，are ubiquitously expressed throughout the nervous system，including in the cerebrovascular smooth muscle cells （CVSMC） and neurons in the brain. CLC-3 chloride channels play critical roles in the regulation of vascular tone and cell volume regulation，migration，proliferation，and apoptosis. Remodeling of CLC-3 Cl- channels in CVSMC contributes significantly to the development of vascular pathology and remodeling and may be novel mechanisms for hypertension and stroke. Targeting Cl- channels may be a novel therapeutic strategy for the treatment of hypertension and stroke. CLC-3 Cl- channels are also involved in neuronal apoptosis and are important regulators of cell volume and hippocampal neuronal apoptosis. Expression of CLC-3 in the presynaptic vesicles determines quantal size of inhibitory transmission in the hippocampus through impact on GABAergic synaptic transmission. A distinct presynaptic CLC-3 dependent regulatory mechanism may represent a novel target for the regulation of synaptic vesicle acidification and filling. It extends the role of Cl- in inhibitory transmission from that of a postsynaptic permeant species to a presynaptic regulatory element. The CLC-3 Cl- channels are important targets for glioma and cancer therapy. CLC-3 channels （Cl.vol）/transporters may play important roles in the regulation of many cellular functions and integrate their physiological and pathological roles with multi-chloride channels，including TMEM16A（ Cl.ca），CFTR at the phenomic level in the cerebrovascular and nervous system. Deep understandings of CLC-3 Cl- channels expression and function in the nervous system may provide novel molecular insights into the cerebrovascular disease and brain disease including brain cancers.