Mechanisms of plasticity are important to the astounding capacity of the brain to adapt and learn. Ion channels are significant contributors to neuronal plasticity, but their dysfunction has been implicated in several nervous system diseases from movement disorders to epilepsy. Although many inherited ion channel mutations have been associated with these disorders, it has been recently recognized that channelopathies can also include aberrant ion channel function that is acquired after an insult or injury to the brain. These acquired alterations are being investigated in animal models of temporal lobe epilepsy, where studies have shown functional changes in voltage-gated ion channels that lead to increases in excitability. Studies of these hyperexcitable neurons have included recordings in the hippocampus, entorhinal cortex, and thalamus and support the existence of an extended seizure network with several nodes of altered activity that are established during epileptogenesis. A better understanding of the key ion channels and brain regions that are responsible for the development of this hyperexcitability, along with the molecular mechanisms involved, may provide novel treatment strategies for epilepsy.