The mechanisms underlying mesial temporal lobe epilepsy (MTLE) remain uncertain. Putative mechanisms should account for several features characteristic of the clinical presentation and the neurophysiological and neuropathological abnormalities observed in patients with intractable MTLE. Synaptic reorganization of the mossy fiber pathway has received considerable attention over the past two decades as a potential mechanism that increases the excitability of the hippocampal network through the formation of new recurrent excitatory collaterals. Morphological plasticity beyond the mossy fiber pathway has not been as thoroughly investigated. Recently, plasticity of the CA1 pyramidal axons has been demonstrated in acute and chronic experimental models of MTLE. As the hippocampal formation is topographically organized in stacks of slices (lamellae), synaptic reorganization of CA1 axons projecting to subiculum appears to increase the connectivity between lamellae, providing a mechanism for translamellar synchronization of cellular hyperexcitability, leading to pharmacologically intractable seizures.