ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloproteinase specialized in the degradation of chondroitin sulfate proteoglycans, contributing to cartilage breakdown during arthritis. In this review, we first focus on the modifications of ADAMTS-4 expression during CNS physiological and pathological conditions, including chronic diseases and injuries. Then, we discuss the contributions of ADAMTS-4 to mechanisms mediating neuroplasticity, neuroinflammation and neurodegeneration during spinal cord injury, ischemic stroke, amyotrophic lateral sclerosis and Alzheimer's disease. Here, we provide an overview of ADAMTS-4 functions and effects in the CNS, and we discuss directions for future studies and treatments. Overall, this review highlights that ADAMTS-4 is a unique multifaceted metalloproteinase which influences various CNS disease pathophysiologies. © 2017 Wiley Periodicals, Inc.