The molecular mechanisms of learning and memory, and the underlying bidirectional changes in synaptic plasticity that sustain them largely implicate protein kinases and phosphatases. Specifically, Ca2+-dependent kinases and phosphatases actively control neuronal processing by forming a tightly regulated balance in which they oppose each other. In this balance, calcineurin (PP2B) is a critical protein phosphatase whose main function is to negatively modulate learning, memory, and plasticity. It acts by dephosphorylating numerous substrates in different neuronal compartments. This review outlines some of CN neuronal targets and their implication in synaptic functions, and describes the role of CN in the acquisition, storage, retrieval, and extinction of memory, as well as in bidirectional plasticity. (C) 2003 Elsevier Inc. All rights reserved.