Despite advances in the techniques of ‘off-pump’ Cardiac surgery, the vast majority of cardiac operations still involve using cardiopulmonary bypass (CPB) along with some form of myocardial protection. The extracorporeal circuits used in the modern bypass-machine have developed considerably in the last few decades. However contact activation of blood leading to a systemic inflammatory response is to some degree inevitable. Although often remaining sub-clinical and resolving promptly at the end of CPB, in its most extreme form this inflammatory response may be associated with the development of the systemic inflammatory response syndrome (SIRS) that can often lead to major organ dysfunction syndrome (MODs) and death. Here we review the pathophysiology behind the development of this “whole body” inflammatory response and consider the mechanical and pharmacological methods that are currently used to minimise it.