Tissue-type plasminogen activator (tPA) is a serine protease well known to promote fibrinolysis. This is why: its recombinant form (rtPA) can be used, either alone or combined with thrombectomy, to promote recanalization/reperfusion following ischemic stroke. However, its overall benefits are counteracted by some of its side-effects, including incomplete lysis of clots, an increased risk of hemorrhagic transformation and the possibility of neurotoxicity. Nevertheless, better understanding of the mechanisms by which tPA influences brain function and promotes its alteration may help in the design of new strategies to improve stroke therapy.