Biomaterials used as implants and in various devices must exhibit long-term (years) compatibility with the physiological environment, including blood, and additionally must also remain stable to perform mechanical functions, excepting applications where biodegradation is required. This paper focuses on problems and challenges of polymeric materials in contact with blood in the following categories: (1) artificial heart valves, (2) cardiovascular assist devices and artificial hearts, (3) vascular prostheses, and (4) the biological evaluation of materials prior to their human use, especially with respect to species related hematological differences of experimental animals. Besides thrombosis (which is the most obvious consequence of incompatibility), the calcification of chemically treated tissue prostheses as well as synthetic elastomers used in many cardiovascular devices is discussed in terms of biochemical and physico-chemical parameters together with its significance in long-term (years) implant applications. Complement activation brought about by contact of blood with foreign surfaces has received less than deserved attention in the evaluation of biomaterials and devices, despite the potentially serious problems. Relative ignorance in selecting appropriate animals for the biological evaluation of biomaterials whose hematological profiles and behavior of platelets, red and white cells to trauma and response to foreign surfaces differ decisively from those of humans, often leads to less than meaningful predictions for eventual clinical uses. The state-of-art realities are examined in conjunction with medical, societal, ethical, and economic boundaries.