Calmodulin-kinase II (CaM kinase) is a calcium/calmodulin-dependent protein kinase which is highly enriched in the nervous system and mediates many of calcium's actions. Regulation of CaM kinase activity plays an important role in modulating synaptic transmission, synaptic plasticity and in neuropathology. Primary regulation of CaM kinase occurs via changes in intracellular calcium concentrations. Increased calcium stimulates protein kinase activity and induces autophosphorylation. Autophosphorylation of CaM kinase at specific sites results in altered activity and responsiveness to subsequent changes in calcium concentrations. Intracellular translocation of CaM kinase also appears to result from autophosphorylation. These mechanisms of regulation play an important role in synaptic plasticity (e.g., Aplysia ganglia), status epilepticus and cerebral ischemia. Long-lasting alterations in the expression of CaM kinase have been demonstrated in the kindling model of epilepsy and in monocular deprivation and therefore modulation of gene expression, in addition to autophosphorylation and translocation, appears to be another important mechanism of regulating CaM kinase activity.