The matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular proteases that have been implicated in CNS development and disease. Crucial homeostatic regulation of MMPs is mediated through the expression and actions of the tissue inhibitors of metalloproteinases (TIMPs). Although the TIMPs are recognized inhibitors of the MMPs, recent studies have revealed that these proteins also can exhibit biological activities that are distinct from their interactions with or inhibition of the MMPs. With our understanding of the roles of the TIMPs in the CNS continuously emerging, this review examines the current state of knowledge regarding the multifarious and novel functions of this family of proteins, with particular attention to their increasing potential in the development, plasticity, and pathology of the CNS. © 2003 Wiley-Liss, Inc.