1. The unique biochemical properties of Ca(2+)/calmodulin (CaM)-dependent protein kinase II have made this enzyme one of the paradigmatic models of the forever searched "memory molecule." 2. In particular, the central participation of CaMKII as a sensor of the Ca(2+) signals generated by activation of NMDA receptors after the induction of long-term plastic changes, has encouraged the use of pharmacological, genetic, biochemical, and imaging tools to unveil the role of this kinase in the acquisition, consolidation, and expression of different types of memories. 3. Here we review some of the more exciting discoveries related to the mechanisms involved in CaMKII activation and synaptic plasticity.