The demographic of cardiac surgery patients continues to evolve to include older, sicker candidates, all the while maintaining an expectation of excellent outcomes. These latter results can only be achieved by the parallel advancement and re-examination of the technology of cardiopulmonary bypass (CPB); the key tool used daily by surgical teams worldwide. In this review, we will provide an overview of integrated therapeutic strategies that can be utilized to minimize the complex and myriad changes related to inflammation after CPB with the understanding that this may abrogate the detrimental end-organ and systemic effects of blood activation. Therapeutic strategies specifically related to the technology can be classified into those targeting biomaterial dependent or independent processes. The former can be addressed by the utilization of currently available biocompatible surfaces such as with heparin-coated circuits, phosphorylcholine-coated circuits ('biomembrane mimicry') and circuits composed of copolymers containing surface-modifying additives. The most important strategies related to biomaterial independent activation include the modification of techniques related to cardiotomy blood management and blood filtration. Finally, all of these strategies must be integrated and tailored with complementary pharmacologic agents such as aprotinin and steroids to optimize anti-inflammatory synergism. Only if we are armed with a comprehensive knowledge of the molecular and cellular basis for these strategies will we be able to continue to evolve our treatment in parallel with our patients to achieve these goals.