During the last two decades, reperfusion therapy in acute ischemic stroke has significantly changed the evolution of patients with acute ischemic stroke; the most important limitations of reperfusion by fibrinolytic agents (rtPA) are the short duration of the therapeutic window for these drugs, their relative inefficiency in large arteries proximal occlusions and their potential adverse effects, mainly beyond this narrow therapeutic window. The development of the modern endovascular thrombectomy techniques have shown major advantages and improved clinical benefits in the acute ischemic stroke. Due to clinical reasons and limited accessibility to such endovascular treatments, the present international guidelines for acute ischemic stroke recommend as first line therapy still the tPA fibrinolysis if the patients are inside the therapeutic window, which may be followed by endovascular thrombectomy if there is no significant clinical improvement at the end of the infusion with tPA, due to the longer therapeutic window and higher complexity of the procedure for thrombectomy. The data from the scientific experimental research and clinical observations, including our clinical experience, support the idea that beyond the above mentioned reasons, there are also some delayed clinical benefits beyond immediate fibrinolysis of initial therapy with tPA, based probably on some pharmacologic and biologic properties of tPA and the individual particularities of the microvascular and collateral circulation in the brain of patients with acute ischemic stroke.