- Summary: The entorhinal cortex–hippocampus complex is believed to be the site of origin of seizure activity in the majority of patients with temporal lobe epilepsy (TLE). Both these regions are enriched with cholinergic innervation, which plays a key role in the normal control of neuronal excitability and in higher cognitive processes. In TLE, anatomical and functional changes occur in all cellular components of the local neural circuit. Thus, while it is not surprising that cholinergic functions are altered in the epileptic temporal lobe, the exact nature and role of these changes in the pathogenesis of the disease are not known. In this report, we summarize the scientific background and experimental data supporting a “cholinergic hypothesis of TLE.” We conclude that while the exact role of cholinergic dysfunction in TLE is not known, there is a firm basis for suggesting that changes in the expression of key cholinergic proteins—and the associated cholinergic dysfunction—are key factors in the basic mechanisms underlying TLE.