Despite major improvements in perfusion techniques over the past 50 years, it is still not possible to formulate a clear definition of what is meant by optimal perfusion. In part this is due to the lack of sufficient evidence-based data and in part because of the complex pathophysiology that takes place during cardiac surgery with cardiopulmonary bypass. To find an answer we need to understand the exact mechanism of the inflammatory reaction triggered by the cardiopulmonary bypass. However, it is clear that further improvement of the cardiopulmonary bypass components alone will be sufficient. Only a combined strategy can further improve cardiopulmonary bypass-related morbidity and mortality. Such a combined strategy will embrace perfusion techniques as well as a pharmacological approach. It will also require a continuous monitoring of the microcirculation. The latter will not only allow to rapidly sense changes in the quality of perfusion but, even more important, also make it possible to intervene at the moment of deterioration. Recent research shows that such an approach has positive an impact on cardiopulmonary bypass-related morbidity postoperatively.