Thrombosis associated with blood-contacting devices is a complex process involving several component interactions that have eluded precise definition. Extensive investigations of individual biological modules such as protein adsorption, coagulation cascade activation and platelet activation/adhesion/aggregation have provided an initial foundation for developing biomaterials for blood-contacting devices, but a material that is intrinsically non-thrombogenic is yet to be developed. The well-recognized association between fluid dynamics parameters such as shear stress, vortices, stagnation and thrombotic processes such as platelet aggregation and coagulation aggravate thrombosis on most device geometries that elicit these flow disturbances. Thus, antithrombotic drugs that were developed to treat thrombosis associated with vascular diseases such as atherosclerosis have also been adapted to mitigate the risk of device thrombosis. However, balancing the risk of bleeding with the antithrombotic efficacy of these drugs continues to be a challenge, and surface modification of devices with these drug molecules to mitigate device thrombosis locally has been explored. Pre-clinical blood flow models to test the effectiveness of these drug-device combinations have also evolved and several in-vitro, ex-vivo, and in-vivo test configurations are available with their attendant merits and limitations. Despite considerable efforts toward iterative design and testing of blood contacting devices and antithrombogenic surface modifications, device thrombosis remains an unsolved problem.