Summary. Background: The first generation of clinical reperfusion treatment, intravenous (IV) fibrinolysis with tissue plasminogen activator (tPA), was a transformative breakthrough in stroke care, but is far from ideal. Objectives: To survey emerging strategies to increase the efficacy and safety of cerebral reperfusion therapy. Methods: Narrative review. Results and Conclusions: Innovative IV pharmacologic reperfusion strategies include: extending IV tPA use to patients with mild deficits; developing novel fibrinolytic agents (tenecteplase, desmetolplase, plasmin); using ultrasound to enhance enzymatic fibrinolysis; combination clot lysis therapies (fibrinolytics with GPIIb/IIIa agents or direct thrombin inhibitors); co-administration of MMP-9 inhibitors to deter haemorrhagic transformation; and prehospital neuroprotection to support threatened tissues until reperfusion. Endovascular recanalisation strategies are rapidly evolving, and include intra-arterial fibrinolysis, mechanical clot retrieval, suction thrombectomy, and primary stenting. Combined approaches appear especially promising, using IV fibrinolysis to rapidly initiate reperfusion, mechanical endovascular treatment to debulk large, proximal thrombi, and intra-arterial (IA) fibrinolysis to clear residual distal thrombus elements and emboli.