Activity-dependent remodeling of neural connections might require localized extracellular proteolysis. The tissue-type plasminogen activator (tPA)-plasmin proteolytic system is expressed in different regions of the central nervous system, in the context of a variety of physiological and pathological processes. Accumulating evidence regarding the expression and role of tPA and its inhibitors suggests that extracellular proteolysis is a key player in the biology of memory, emotions and neurodegeneration.