Epileptic seizures will normally arrest abruptly and spontaneously, and the brain will remain refractory to further seizures for some time thereafter. This paper reviews the possible mechanisms underlying this seizure arrest and refractoriness. The data suggests that neuronal fatigue is not involved in either of these processes, whereas the role of ions and excitatory systems are unclear. Rather, seizure arrest and refractoriness may come about by the seizure-induced release and/or activity of multiple endogenous anticonvulsant substances. The spontaneous arrest of the seizure may involve the purine adenosine, in addition to other unknown mechanisms. Seizure refractoriness involves multiple systems, the most important of which, on the available evidence, are prostaglandins and opioid peptides and possibly benzodiazepine systems, although other neuropeptides and the purines may also be involved. The implications of these conclusions to anti-epileptic drug development and status epilepticus are discussed.