Much has been learned about the activity-dependent synaptic modifications (long-term potentiation and long-term depression) that are thought to underlie memory storage, but the mechanism by which these modifications are stored remains unclear. A good candidate for the storage mechanism is Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) because it is localized at synapses, and its known autophosphorylation properties enable it to undergo long-term modification. In this review, John Lisman describes recent tests of the role of CaM kinase II in long-term potentiation. Experiments show that activity of CaM kinase II is increased for long periods of time after induction of long-term potentiation, that enhanced activity mimics long-term potentiation, and that enzyme activity is necessary for induction of long-term potentiation. The crucial question remaining is whether persistent enzyme activity is necessary to maintain stored information. Related issues concerning the mechanism by which synapses are weakened and the role of gene expression and structural changes are also discussed.