Proteolytic regulation might be essential in neural plasticity in mature brain as well as the developing brain. An increasing number of studies support the idea that structural changes in the synapses are closely associated with synaptic plasticity. Proteases and their inhibitors in a synaptic microenvironment are important in the regulation of dynamic changes in the extracellular matrix components associated with synaptic plasticity. In the present article, the possible roles of neuronal proteases, protease inhibitors and extracellular macromolecules are reviewed.