Cardiac surgery has been routinely performed using cardiopulmonary bypass (CPB) ever since its clinical introduction during the 1950s. CPB is, however, associated with an intense inflammatory response because of conversion to laminar flow, blood contact with the artificial bypass surface, cold cardiac ischaemia and hypothermia. The inflammatory reaction can intensify to a systemic inflammatory response syndrome (SIRS) associated with serious morbidity and mortality. Strategies to suppress inflammation had some success but fell short of controlling SIRS. The development of cardiac immobilization techniques allowing complete revascularization has caused a renaissance of coronary artery bypass grafting surgery on the beating heart (OPCAB). This strategy avoids all inflammation caused by CPB and reduces the pro-inflammatory stimulus to sternotomy and the revascularization procedure itself. This review summarises the pathophysiological features of the inflammatory response to CPB, revisits therapeutic anti-inflammatory strategies designed to suppress CPB-induced inflammation and balances the clinical evidence available comparing off-pump and on-pump revascularization.