Research on the molecular and cellular basis of learning and memory has focused on the mechanisms that underlie the induction and expression of synaptic plasticity. There is increasing evidence that structural changes at the synapse are associated with synaptic plasticity and that extracellular matrix (ECM) components and cell adhesion molecules are associated with these changes. The functions of both groups of molecules can be regulated by proteolysis. In this article we review the roles of selected proteases and protease inhibitors in perisynaptic proteolysis of the ECM and synaptic adhesion proteins and the impact of proteolysis on synaptic modification and cognitive function.