Matrix metalloproteinases (MMPs) are a large family of ubiquitous extracellular endopeptidases, which play important roles in a variety of physiological and pathological conditions, from the embryonic stages throughout adult life. Their extraordinary physiological “success” is due to concomitant broad substrate specificities and strict regulation of their expression, activation and inhibition levels. In recent years, MMPs have gained increasing attention as significant effectors in various aspects of central nervous system (CNS) physiology. Most importantly, they have been recognized as main players in a variety of brain disorders having different etiologies and evolution. A common aspect of these pathologies is the development of acute or chronic neuroinflammation. MMPs play an integral part in determining the result of neuroinflammation, in some cases turning its beneficial outcome into a harmful one. This review summarizes the most relevant studies concerning the physiology of MMPs, highlighting their involvement in both the developing and mature CNS, in long-lasting and acute brain diseases and, finally, in nervous system repair. Recently, a concerted effort has been made in identifying therapeutic strategies for major brain diseases by targeting MMP activities. However, from this revision of the literature appears clear that MMPs have multifaceted functional characteristics, which modulate physiological processes in multiple ways and with multiple consequences. Therefore, when choosing MMPs as possible targets, great care must be taken to evaluate the delicate balance between their activation and inhibition and to determine at which stage of the disease and at what level they become active in order maximize chances of success.