Platelets play a key role in arterial thrombosis, a frequent and life-threatening condition. Upon vascular injury, platelets are rapidly recruited to the site of endothelial disruption, where they become activated and critically contribute to the formation of an occlusive clot. To treat or prevent arterial thrombosis, various antiplatelet therapies have been developed. However, most pathways targeted in clinical practice are also involved in hemostasis. Their inhibition, therefore, poses an increased risk of bleeding. To date, it remains an eminent task to identify thrombosis-specific pathways in arterial thrombosis. Platelet receptors and intracellular molecules, whose absence does not cause overt bleeding in humans, may uncover new therapeutic avenues. We here recapitulate the pathophysiology of arterial thrombosis and present recently identified pathways, which reduce pathological thrombosis without affecting hemostatic capacity and thus may serve as future drug targets. Finally, we discuss the reciprocal interactions of platelets and innate immune cells and their potential role in arterial thrombosis. A detailed understanding of the complex mechanisms underlying this life-threatening condition is crucial for future research and the development of novel therapeutic approaches.