Matrix metalloproteinases (MMPs) are a family of extracellular proteases associated with extracellular matrix remodeling. They are involved in many physiological and reparative processes. MMPs can break down all extracellular constituents; therefore, their expression is very tightly regulated and their abnormal activity or over production has been linked to many diseases including multiple sclerosis (MS) which is a leading cause of non-traumatic disability in young adults in North America. Recently many studies, both in animals and humans, have been conducted to better elucidate the underlying causes, mechanisms and pathophysiology of MS. In this review, we discuss the potential role of pathological upregulation of MMPs in MS and future challenges which if properly addressed might help in development of potential cure for this disease.