Major improvements in heart assist devices have allowed prolonged mechanical circulatory support with successful subsequent weaning or heart transplantation. The contact of blood with biomaterials used in life-sustaining devices and numerous biomaterial-independent factors elicit a systemic inflammatory response, which involves activation of various plasma protein systems and blood cells. Prolonged mechanical circulatory support elicits a systemic inflammatory response and hemostatic perturbations similar to that reported during cardiopulmonary bypass. However, in the setting of prolonged assistance, time has a complex and ill-known influence on blood activation. Methods to reduce blood activation during prolonged assisted circulation are derived from cardiopulmonary bypass investigations. Improving the biocompatibility of artificial devices can be achieved either by biomaterial surface modifications, by inhibition of biologic cascades leading to blood activation, or by controlling end points of biologic cascades. However, the necessity to respect the integrity of the organism during prolonged assistance precludes most systemic interventions and limits the control of blood activation to the area of the device.