Calcium/calmodulin-stimulated autophosphorylation of a prominent brain calmodulin-dependent protein kinase (Type II CaM kinase) produces dramatic changes in its enzymatic activity. These changes suggest a mechanism by which the kinase could act as a calcium-triggered molecular switch. Incorporation of 3-12 of a possible total of 30 phosphate groups per holoenzyme causes kinase activity toward exogenous substrates as well as autophosphorylation itself to become independent of calcium. Thus, kinase activity could be prolonged beyond the duration of an initial activating calcium signal. The calcium-independent autophosphorylation could further prolong the active state by opposing dephosphorylation by cellular phosphatases.