Red blood cells (RBCs) are important for the supply of oxygen but also play a role in hemostasis and thrombosis by platelet activation and thrombus formation. They release ATP/ADP and force platelets to the vessel wall by rheological mechanisms. Furthermore, RBCs have phosphatidylserine (PS) on the cell surface to enhance thrombin generation. The procoagulant activity is mediated—at least in part—by the interaction of RBCs with platelets via FasL/FasR signaling, thereby enhancing thrombus formation and stabilization. Besides, extracellular vesicles derived from RBCs promote thrombus formation. Moreover, RBCs influence the fibrin network and, as a result, provoke thrombotic events, suggesting an important role in different cardio and cerebrovascular diseases, as well as in polycythemia vera. Besides their thrombotic potential, RBCs promote platelet-mediated thrombo-inflammation, oxidative stress, and hypoxia. In abdominal aortic aneurysm (AAA), RBC hemolysis and hemoglobin release within the growing intraluminal thrombus (ILT) might reflect a newly discovered mechanism of how RBCs mediate platelet activation and recruitment in the ILT and thereby promote AAA pathology. However, the role of RBCs in cardiovascular and cerebrovascular diseases is still undervalued, and it is believed that there are several yet unknown mechanisms of how RBCs communicate with platelets upon thrombus formation by direct and indirect mechanisms. So far, there is no direct therapy available targeting platelet-RBC interaction in thrombotic diseases, although RBCs are present in different thrombi in arteries and veins. This suggests a great potential for promising anti-thrombotic therapies. Moreover, RBCs represent natural carriers of vascular drug delivery and are a promising target of thrombolytic therapies. However, the identification of further RBC-platelet interaction upon thrombosis will be of great importance for new, specific anti-thrombotic therapies in the near future.