Patient-level health outcomes for acute ischemic stroke have significantly improved in the last decade primarily because of superior overall case management, availability of tailored drug interventions, and advances in endovascular procedures. Nevertheless, disease registries show a "quality gap" across social determinants of health and between in-hospital and community-onset strokes. Several factors, including financing and infrastructure constraints, limited expertise, and clinical uncertainty, still prevent adherence to evidence-based clinical guidelines and optimal care pathways. This paper critically appraises existing evidence on the use of drug therapies in acute ischemic stroke, in an attempt to resolve physician-related subjective barriers for effective acute management of the disease. We conclude that intravenous administration of rt-PA (recombinant tissue-type plasminogen activator, alteplase) is an essential component of acute-phase pharmacologic treatment and a driver for the improvement of overall ischemic stroke health outcomes. The safety profile of alteplase and similar treatments are well within the patient benefit zone of eligible patients when compared to non-treatment alternatives. Monomodal neuroprotective drugs with single or pleiotropic mechanisms of action have failed to support long-term sustainable results. Drugs with complex mechanisms of action that promote neurorecovery, such as cerebrolysin, are valid options for adjunctive treatment of acute ischemic stroke. Recent years have shown clear improvements in the methodology and design of clinical trials, with an increase in overall internal and external validity. A better understanding of study limitations has not hindered, but enhanced their potential to contribute, together with sometimes superior data sources, to health decision making.