Existing members of the anti-epileptic drug (AED) class often fail to provide meaningful symptom relief to patients experiencing persistent pain, epilepsy and other neurological disorders, and can evoke substantial adverse events. In an effort to improve treatment options, much attention has turned to novel mechanisms that may represent points of therapeutic intervention. Among these mechanisms are the cation-chloride co-transporters (CCCs), the dysfunction of which has been linked to aberrant chloride homeostasis in neurons of the CNS, and resulting disorders including persistent pain and epilepsy. This review examines the literature linking CCCs to neurological disease, and discusses their considerable potential as the basis for novel therapeutic strategies.