Human disease-causing mutations and genetically modified mouse models have established the importance of KCC2 and KCC3 in nervous system physiology. These two proteins mediate the electroneutral cotransport of K and Cl ions across the neuronal membrane. Disruption of KCC2 function affects inhibitory synaptic transmission with consequences for epilepsy, pain perception, and potentially some neuropsychiatric disorders, whereas disruption of KCC3 affects both central and peripheral nervous systems, resulting in psychosis and peripheral neuropathy. Until recently, the KCC field has suffered from an almost complete lack of pharmacological tools with which to probe cotransporter function. The only available tools being the very poorly potent loop diuretics (e.g., furosemide EC = 6 × 10 M). To address this deficiency, efforts that focused on the discovery of KCC modulators have been undertaken. This work has resulted in the discovery of novel inhibitory compounds that are up to four orders of magnitude more potent (EC = 6 × 10 M) and with increased specificity. While useful for ex vivo studies, these tools possess poor pharmacokinetic properties, severely limiting their utility in vivo. In addition, only a few agents acting on regulatory molecules have been identified as putative KCC activators. Thus, further research is required to develop tools suitable to advance our understanding of how KCC modulation may be useful for the treatment of disease.