Acute ischemic stroke (AIS) and myocardial infarction are the major causes of death and disability worldwide. Rapid restoration of blood flow by pharmacological thrombolysis and/or endovascular thrombectomy (EVT) is the mainstay of acute stroke treatment, but does not guarantee a favorable outcome. Ischemia/reperfusion (I/R) injury denotes the acute, paradoxically harmful aspect of blood flow return in the ischemic brain which is now recognized to at least partly occur through a platelet-driven pathomechanism commonly referred to as thrombo-inflammation. Hereby, platelets orchestrate immune cell trafficking and activation, with ensuing disturbance of blood-brain barrier function and edema formation, ultimately leading to ongoing neuronal cell death and infarct growth despite recanalization. Simultaneously, platelets are essential to prevent inflammatory bleeding in the postischemic cerebral tissue by mechanisms that are not fully understood, but independent of platelet aggregation. In experimental stroke, the immunoregulatory platelet adhesion receptors glycoprotein (GP)Ibα and GPVI were required for platelet and immune cell recruitment to the postischemic brain endothelium. Accordingly, blocking of platelet GPIbα or GPVI dramatically improved stroke outcome by protecting from I/R injury, as well as from infarct progression already under large vessel occlusion before recanalization. Despite interfering with this thrombo-inflammatory platelet activity, no bleeding complications occurred, in contrast to devastating intracranial hemorrhages observed after blocking platelet aggregation via GPIIb/IIIa. The ACTIMIS trial targeting platelet GPVI by glenzocimab in AIS as adjunct treatment to thrombolysis provided encouraging safety signals, but was not powered to show clinical efficacy. The MOST trial targeting GPIIb/IIIa or thrombin most recently failed. It will be essential to further dissect thrombo-inflammatory platelet functions and activation pathways from those indispensable as gatekeepers of hemostasis in the stroke-injured brain and to translate experimental findings to the clinic.