This review examines the clinical data and basic science research to evaluate the potential of the Selective Cytopheretic Device (SCD) in mitigating Extracorporeal Membrane Oxygenation (ECMO)-associated inflammation. In brief, SCD is an immunomodulatory device used within extracorporeal blood circuits along with the use of citrate anticoagulation. SCD has been shown to be a novel, first-in-its-class device (being marketed as QUELimmune by SeaStar Medical), which is capable of the autologous processing of hyper-inflamed leukocytes to reduce systemic inflammation. Strong preclinical data gathered for SCD in the context of both Cardio-Pulmonary Bypass (CPB) as well as ECMO set the stage for SCD to be used in these life support circuits. ECMO played a crucial role during the COVID-19 pandemic, during a time period when SCD therapy was being evaluated in clinical trials, generating initial clinical data in this setting. SCD has also been utilized in the setting of pediatric acute kidney injury (AKI) and multiorgan dysfunction (MOD), where ECMO can be common.