Cation-chloride cotransporters exert a major influence on the neuronal intracellular chloride concentration. Thereby, they are crucial for the Cl-dependent signalling mediated by GABAA and glycine receptors. Short-term and long-term changes in [Cl-]i based on changes in the activity of the chloride transporters lead to ionic plasticity, i.e. quantitative and qualitative changes in the action of GABA and glycine. Such changes in inhibitory signalling occur during development, when a shift from relatively high intracellular Cl- levels towards lower levels is seen in most central neurons. In addition, such changes may also contribute to pathological neuronal activity, e.g., epilepsy (Kahle et al., 2008; Blaesse et al., 2009). KCC2, a K-Cl cotransporter, is the main Cl- extruder in central neurons and responsible for an inwardly-directed Cl- electrochemical gradient that is required for classical hyperpolarizing GABAergic inhibition. Numerous studies have shown that posttranslational modifications play a pivotal role in the short-term regulation of the transporter under physiological and pathophysiological conditions. Mimicking certain aspects of human epilepsy in animal models and in vitro revealed new molecular mechanisms involved in the fast regulation of KCC2. In contrast to the known down-regulation of KCC2 by increased neuronal activity in mature neurons, a single seizure episode led to a rapid activation of KCC2 in the neonatal rat hippocampus, when KCC2 is not yet active under control conditions (Khirug, Ahmad et al., 2010). The activity-dependent functional up-regulation of KCC2 in immature neurons was paralleled by an increase in KCC2 surface expression. Signalling via the TrkB tyrosine kinase was essential for the activity-induced changes in KCC2-mediated Cl- transport and KCC2 trafficking. Interestingly, TrkB signalling is also crucial for the activity-dependent down-regulation of KCC2 in the more mature system, pointing to a developmental sign change within the TrkB-KCC2 signalling cascade. In addition to changes in trafficking, activity-dependent cleavage of KCC2 by the plasticity-associated protease calpain has been identified as a new mechanism for the fast functional down-regulation of KCC2 (Puskarjov, Ahmad et al., 2012). The application of the glutamate receptor agonist NMDA or the induction of interictal-like activity led to a fast reduction of KCC2 protein level and of KCC2-mediated Cl- transport in hippocampal CA1 neurons. Both effects were blocked by inhibitors of the calcium-activated protease calpain. The role of the different mechanisms and of the resulting ionic plasticity of GABAergic signalling under physiological (e.g., in learning-associated synaptic plasticity) and pathological conditions will be discussed.