Dystrophin is a cytosolic protein belonging to a membrane-spanning glycoprotein complex, called dystrophin-glycoprotein complex (DGC), that is expressed in many tissues, especially in skeletal muscle and in the nervous system. The DGC connects the cytoskeleton with the extracellular matrix and, although none of the protein of the DGC displays kinase or phosphatase activity, it is involved in many signal transduction pathways. Mutations in some components of the DGC are linked to many forms of inherited muscular dystrophies. In particular, a mutation hitting the dystrophin gene, leading to a complete loss of the protein, provokes one of the most prominent muscular dystrophy, the Duchenne muscular dystrophy, which affects 1 out of 3500 newborn males. In these circumstances, it can be observed a dramatic alteration of the expression levels of a multitude of metalloproteinases (MMPs), a family of extracellular Zn2+-dependent endopeptidases, especially MMP-2 and MMP-9, also called gelatinases. However, the enzymatic activity of MMP-2 and MMP-9 on dystroglycan, an important member of the DGC, plays an important role also in physiological processes taking place in the central and peripheral nervous system. This mini-review discusses the role of MMP-2 and MMP-9, in physiological as well as pathological processes involving members of the DGC.