There are four unresolved clinical issues at bedside with respect to the recognition, differential diagnosis, prognosis, and treatment of infants who present with seizures. There is also an overriding fifth question which bridges these four clinical issues, based on a laboratory researcher's perspective at the “bench”. Given the increasing understanding of the neurobiologic and pathophysiologic explanations for seizures in animal models, one must consider the question of whether neonatal seizures cause brain injury or are a surrogate of injury resulting from other etiologies.