Despite rapid advances in cardiovascular technology, none of the cardiovascular materials in clinical use can fulfill all the requirements of blood compatibility. To overcome unfavorable material-related biological responses, surface modification strategies enable the combination of material bulk properties with the desired biological attributes of low activation of hemostatic and inflammatory processes. This chapter presents current concepts to reduce surface-initiated incompatibility reactions either by selection of surface modifications with low activation potential or by active pharmacologic targeting of the biological pathways, and by the combination thereof. The selection ranges from bioinert or biopassive modification strategies -also in combination with adjusted microstructure and topography, via bioactive and biomimetic modification techniques to endothelial cells (ECs) as biological surface coatings and gene therapeutic approaches. Surface modifications, which support the homeostasis of specific parameters in coagulation and inflammation, or which stimulate the adsorption of anticoagulant and fibrinolytic proteins or the adhesion of ECs and their progenitors are seen as the main future trends.