Epilepsy is a common, chronic neurologic disorder characterized by recurrent unprovoked seizures. Experimental modeling and clinical neuroimaging of patients has shown that certain seizures are capable of causing neuronal death. Such brain injury may contribute to epileptogenesis, impairments in cognitive function or the epilepsy phenotype. Research into cell death after seizures has identified the induction of the molecular machinery of apoptosis. Here, the authors review the clinical and experimental evidence for apoptotic cell death pathway function in the wake of seizure activity. We summarize work showing intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathway function after seizures, activation of the caspase and Bcl-2 families of cell death modulators and the acute and chronic neuropathologic impact of intervening in these molecular cascades. Finally, we describe evolving data on nonlethal roles for these proteins in neuronal restructuring and cell excitability that have implications for shaping the epilepsy phenotype. This review highlights the work to date on apoptosis pathway signaling during seizure-induced neuronal death and epileptogenesis, and speculates on how emerging roles in brain remodeling and excitability have enriched the number of therapeutic strategies for protection against seizure-damage and epileptogenesis.