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Highlights: [•] The rapid and reversible phosphorylation and/or dephosphorylation of critical phosphoresidues in the KCC2 cytoplasmic carboxyl terminus constitutes a potent and dynamic set of mechanisms to modulate KCC2 activity. [•] PKC-dependent serine 940 phosphorylation increases KCC2 activity and plasma membrane accumulation by slowing transporter endocytosis. By contrast, WNK kinase-dependent phosphorylation of threonines 906 and 1007 appears to reduce the intrinsic rate of KCC2-mediated ion transport, and dephosphorylation of these residues can activate KCC2. Tyrosine 1087 phosphorylation promotes KCC2 activity by increasing the membrane insertion of transporters. [•] Alterations in the phosphorylation state of these different KCC2 phosphoresidues are variably altered across neurodevelopment and in models of different neurological diseases. [•] These phosphoevents probably function not so much as on/off switches of KCC2 activity, but more as modulators, conferring quantitatively graded levels of KCC2 activity in response to physiological signals and perturbations, thus matching changing levels of neuronal Cl– loads, or increased metabolic demands. [•] Selective modulation of KCC2 phosphoresidues, either directly or indirectly, could represent novel therapeutic strategies for the treatment of epilepsy, neuropathic pain, and spasticity—conditions that have been linked to functional downregulation of KCC2 and, in some instances, have shown an altered phosphorylation profile. [ABSTRACT FROM AUTHOR]