Matrix metalloproteinases (MMPs) play critical roles in egg fertilization, embryonic development, wound repair, cancer, and inflammatory and neurologic diseases. This subfamily of metzincin peptidases can cleave extracellular matrix (ECM) and pericellular proteins that have profound effects on cell behavior. Among known MMP substrates are several proteins that play important roles in synaptogenesis, synaptic plasticity, and long-term potentiation (LTP). In this Mini-Review we discuss how MMP-directed cleavage of these proteins can impact the formation and function of synapses within the brain. Pyramidal neurons in the hippocampus, and other large neurons, are surrounded by perineuronal nets that are composed of brevican, tenascin-R, and laminin, each of which is subject to proteolytic cleavage by MMPs. Tenascin-R knockout mice show deficits in learning and memory and LTP, as do at least two MMP knockouts. Impaired LTP is also seen in brain-derived neurotrophic factor (BDNF) knockout mice, which is interesting in that pro-BDNF can be processed into mature BDNF by several MMPs and thereby regulate activation of the high-affinity BDNF receptor TrkB. At the synaptic level, MMP substrates also include ephrins, Eph receptors, and cadherins, which are also involved in synapse development and plasticity. MMPs can also process membrane-bound tumor necrosis factor-α into a potent soluble cytokine that is increasingly implicated in neuron–glial signaling, particularly in neurologic disease. Finally, we discuss how the development of therapeutics to attenuate MMP activity in neurodegenerative disorders may become powerful tools for future studies of synaptic formation and function within the developing and mature brain. © 2007 Wiley-Liss, Inc.