Hyper-excitability is a permissive factor for the genesis/propagation of epileptic seizures. Aberrant GABAergic neurotransmission may be the cause of inhibition deficits in epilepsy. In many epileptic patients, seizures are controlled with anti-epileptic drugs, including enhancers of GABAergic transmission; however, about 30% of the patients became resistant to the treatment. Pharmacoresistance is associated to changes in neuronal plasticity and alterations of GABA_A receptor (GABA_AR)-mediated neurotransmission. Unpublished results from our laboratory indicate that SE alters GABA_ARs dynamics with a consequent synaptic downregulation. The downregulation of GABA inhibitory activity may arise from a positive shift in GABA_AR reversal potential, due alterations in chloride homeostasis. However, whether alterations in the Cl^– gradient account for the downmodulation of GABAergic neurotransmission in status epilepticus is not yet established. Ongoing studies address the molecular mechanisms underlying the alterations of GABA^_A receptor dynamics and the role of chloride homeostasis in the impairment of the inhibitory synaptic transmission during epilepsy, proposing the K+-Cl-cotransporter (KCC2) as therapeutic target for epilepsy.