In a quest for stroke treatment, reperfusion proved to be the first key to the puzzle. Systemic tissue plasminogen activator (tPA), the first and currently the only approved treatment, is also the fastest way to initiate thrombolyis for acute ischemic stroke. tPA works by induction of mostly partial recanalization since stroke patients often have large thrombus burden. Thus, early augmentation of fibrinolysis and multi-modal approach to improve recanalization are desirable. This review focuses on the following strategies available to clinicians now or being tested in clinical trials: (a) faster initiation of tPA infusion; (b) sonothrombolysis; (c) intra-arterial revascularization, bridging intravenous and intra-arterial thrombolysis, mechanical thrombectomy and aspiration; and (d) novel experimental approaches. Despite these technological advances, no single strategy was yet proven to be a 'silver bullet' solution to reverse acute ischemic stroke. Better outcomes are expected with faster treatment leading to early, at times just partial flow improvement rather than achieving complete recanalization with lengthy procedures. Arterial re-occlusion can occur with any of these approaches, and it remains a challenge since it leads to poor outcomes and no clinical trial data are available yet to determine safe strategies to prevent or reverse re-occlusion.