Extracorporeal life support (ECLS) encompasses a wide range of extracorporeal modalities that offer short- and intermediate-term mechanical support to the failing heart or lung. Apart from the daily use of cardiopulmonary bypass (CPB) in the operating room, there has been a resurgence of interest and utilization of veno-arterial and veno-venous extracorporeal membrane oxygenation (VA- and VV-ECMO, respectively) and extracorporeal carbon dioxide removal (ECCO
2
R) in recent years. This might be attributed to the advancement in technology, nonetheless the morbidity and mortality associated with the clinical application of this technology is still significant. The initiation of ECLS triggers a systemic inflammatory response, which involves the activation of the coagulation cascade, complement systems, endothelial cells, leukocytes, and platelets, thus potentially contributing to morbidity and mortality. This is due to the release of cytokines and other biomarkers of inflammation, which have been associated with multiorgan dysfunction. On the other hand, ECLS can be utilized as a therapy to halt the inflammatory response associated with critical illness and ICU therapeutic intervention, such as facilitating ultra-protective mechanical ventilation. In addition to addressing the impact on outcome of the relationship between inflammation and ECLS, two different but complementary pathophysiological perspectives will be developed in this review: ECLS as the cause of inflammation and ECLS as the treatment of inflammation. This framework may be useful in guiding the development of novel therapeutic strategies to improve the outcome of critical illness.