Stroke is an enormous public health problem with an imperative need for more effective therapy. Recombinant tissue plasminogen activator is the only licensed drug for acute stroke, but its efficacy may be limited by the toxicity of the compound and by reperfusion injury. The coadministration of neuroprotective drugs could augment the value of thrombolytic therapy, but the evidence in support of this approach is scarce. The use of the free radical trapping NXY-059, either with or without recombinant tissue plasminogen activator, was not successful in Phase III studies. However, these results could reflect its weak antioxidant capacity, poor blood-brain barrier penetration, and lack of synergism with recombinant tissue plasminogen activator as well as the overly broad treatment window used in the reported trials. This article contends that further translational research should explore newer antioxidant drugs in combination with thrombolytic agents, but only if the combination yields additive or synergistic effects in preclinical thromboembolic models or in biomarker-assisted Phase II studies. Edaravone and novel nitrones endowed with a better pharmacokinetic profile or multitarget and thrombolytic activity are discussed as well as the latest research data on uric acid, a strong endogenous antioxidant in blood that is early consumed after acute stroke. The coadministration of uric acid and recombinant tissue plasminogen activator has shown to provide synergistic neuroprotection in experimental thromboembolic models and to lessen several biomarkers of oxidative stress in patients with acute stroke. The clinical efficacy of uric acid is currently under investigation in a Phase III trial that follows current recommendations of also evaluating surrogate biomarkers of treatment effects.