Repetitive electrical stimulation and application of excitatory amino acids lead to decreases in extracellular Ca2+ concentration and to rises in extracellular K+ concentration [( Ca2+]o, [K+]o) with a typical laminar distribution in a given neo- or allocortical structure. These ionic changes result from transmembrane ion fluxes along their respective electrochemical gradients. Epileptogenic drugs that impair repolarizing K+ conductances or inhibitory synaptic transmission enhance such extracellular ionic changes, but they do not alter the laminar distribution of [K+]o and [Ca2+]o changes. Enhanced [Ca2+]o concentration changes are also observed in chronic epilepsies such as the chronic alumina cream and cobalt focus, the kindling epilepsy, and during photically induced seizures in the baboon Papio papio. In chronic epilepsies, the sites of maximal [Ca2+]o changes shift to other layers, suggesting changes in the distribution of ion channels over the surface of nerve cells that may be involved in epileptogenesis in chronic epilepsies. The K+ and Ca2+ concentration changes associated with seizure contribute to the generation and spread of epileptic activity. This is demonstrated by the fact that lowering of extracellular free calcium concentration can induce spreading epileptiform activity in the absence of chemical synaptic transmission, with [K+]o rises preceding epileptiform activity.