ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteinases degrade proteoglycans and thereby have the potential to alter tissue architecture and regulate cellular function. Recent studies about the roles of these enzymes have produced new perspectives for the molecular mechanisms behind regenerative biology with clinical potential to generate therapeutic targets to resolve tissue injury. ADAMTS enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their dysregulation has been implicated in disease-related processes such as inflammation and fibrosis. Increasing evidence indicates that they may be of key significance in the physiological and pathological central nervous system. In this review, we summarize what is currently known about the roles of ADAMTS proteins in tissue repair and regeneration as well as in the pathogenesis of other important biological processes and diseases including arthritis, atherosclerosis, and cancer.