The use of blood-contacting implantable devices is limited by surface-induced thrombosis, which has led to the development of thromboresistant surfaces. Multidisciplinary efforts have promoted the development of surface modifications to minimize thrombosis by targeting surface-induced coagulation. To this date, no material has been identified that remains irrevocably hemocompatible with time but many options are now available with their own limitations. Essential to this review is the understanding of some of the challenges in this field and newer opportunities for hemocompatibility research. This report will also briefly review many of the achievements in the development of hemocompatible biomaterial coating, including surface modifications against protein adsorption and platelet adhesion, biomimetism, and endothelialization.