In ischemic stroke, treatment options are limited. Therapeutic thrombolysis is restricted to the first few hours after stroke, and the utility of current platelet aggregation inhibitors, including GPIIb/IIIa receptor antagonists, and anticoagulants is counterbalanced by the risk of intracerebral bleeding complications. Numerous attempts to establish neuroprotection in ischemic stroke have been unfruitful. Thus, there is strong demand for novel treatment strategies. Major advances have been made in understanding the molecular functions of platelet receptors such as glycoprotein Ib (GPIb) and GPVI and their downstream signaling pathways that allow interference with their function. Inhibition of these receptors in the mouse stroke model of transient middle cerebral artery occlusion prevented infarctions without increasing the risk of intracerebral bleeding. Similarly, it is now clear that the intrinsic coagulation factor XII (FXII) and FXI play a functional role in thrombus formation and stabilization during stroke: their deficiency or blockade protects from cerebral ischemia without overtly affecting hemostasis. Based on the accumulating evidence that thrombus formation and hemostasis are not inevitably linked, new concepts for prevention and treatment of ischemic stroke may eventually emerge without the hazard of severe bleeding complications. This review discusses recent advances related to antithrombotic strategies in experimental stroke research.