In this review, we hypothesise that, next to biocompatibility, optimal blood compatibility depends on a combination of biomaterials wettability and the shear stress prevailing in the device. The wettability is discussed in seven different categories of devices, that differ substantially from each other with regard to shear stress and exposure time. These seven categories are stents, prosthetic heart valves, vascular prostheses, cardiopulmonary bypass, hemodialysis, vena cava filters and blood bags. In high shear applications, in combination with blood activation, platelet deposition and thrombosis appear to be major problems and platelet inhibitors are most effective. Exposure of blood to a large biomaterial surface, with or without antithrombotic coating, results in reduction of platelet function. Material-independent activation aggravates this process. In low shear applications, platelets only seem supportive for coagulation and anticoagulants should be used.