Intravenous thrombolysis (IVT), using alteplase or tenecteplase, represents a standard reperfusion therapy of acute ischemic stroke. IVT may nowadays be used not only within a standard 4.5-h time window, but up to 9 h, and also in wake-up strokes and strokes of unknown onset in patients with ischemic penumbra identified using advanced imaging methods (and within 24 h of symptoms onset in basilar artery occlusions, even without advanced imaging). Nevertheless, earlier treatment is associated with better functional outcomes. In patients with large vessel occlusion, the combination of IVT and mechanical thrombectomy is the standard of care. Also, patients treated with IVT despite recent use of direct oral anticoagulants may achieve favorable functional outcomes similar to those not on anticoagulants. Main complications include intracerebral hemorrhage, major systemic bleeding and peripheral hemorrhages, reocclusion, reperfusion injury, and angioedema. Future perspectives include the development of personalized medicine, addressing global accessibility, mobile stroke units, and research innovations.