Tissue-type plasminogen activator (t-PA ) plays an important role in the removal of intravascular fibrin deposits and has several physiological roles and pathological activities in the brain. Its production by many other cell types suggests that t-PA has additional functions outside the vascular and central nervous system. Activity of t-PA is regulated at the level of its gene transcription, its mRNA stability and translation, its storage and regulated release, its interaction with cofactors 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 expression.