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Tissue-type plasminogen activator (t-PA) plays an important role in the removal of intravascular fibrin deposits and has several physio-logical roles and pathological activities in the brain. Its production by many other cell types suggests that t-PA has additional functions out-side the vascular and central nervous system. Activity of t-PA is regu-lated at the level of its gene transcription, its mRNA stability and translation, its storage and regulated release, its interaction with co-factors that enhance its activity, its inhibition by inhibitors such as plasminogen activator inhibitor type 1 or neuroserpin, and its removal by clearance receptors. Gene transcription of t-PA is modulated by a large number of hormones, growth factors, cytokines or drugs and t-PA gene responses may be tissue-specific. The aim of this review is to summarise current knowledge on t-PA function and regulation of its pericellular activity, with an emphasis on regulation of its gene ex-pression