Mortality and morbidity postcardiac surgery with cardiopulmonary bypass (CPB) remain relative stable over the last decades, while the number of patients with increased comorbidity and more complex cardiac disease increases. Nevertheless, end-organ dysfunction and/or failure remain an issue. Multiple perioperative variables, such as non-optimal oxygen delivery, manipulation of the aorta, hyperlactatemia, type of anesthesia, surgical procedure and myocardial protection can be hold responsible for end-organ failure postcardiac surgery. However, it becomes more and more evident that also pre-existing factors, such as metabolic syndrome, renal insufficiency, hypertension, stroke and infection exacerbate mortality and morbidity. Unfortunately, these predisposing risk factors cannot be influenced perioperatively. Therefore, therapy should focus on controlling perioperative variables that, in combination with the predisposing factors, will further exacerbate organ dysfunction. In order to achieve this, more emphasis should be given to a patient-specific, goal-directed perfusion approach. This review will mainly focus on the impact of perioperative variables.