Cardiopulmonary bypass (CPB) activates a well-characterised systemic inflammatory response that contributes substantially to postoperative morbidity and mortality, particularly in high-risk patient subgroups. CytoSorb® (CytoSorbents Corporation, Princeton, NJ) is a polystyrene-divinylbenzene copolymer haemoadsorption device capable of removing hydrophobic molecules of up to 55 kDa, including pro-inflammatory cytokines, myoglobin, bilirubin, and direct oral anticoagulants (DOACs) from whole blood during CPB. Whilst aggregate meta-analyses have not demonstrated consistent benefit across unselected surgical populations, subgroup analyses and targeted clinical series consistently identify meaningful benefit in high-risk phenotypes: infective endocarditis (IE), complex aortic surgery under hypothermic circulatory arrest, heart transplantation, emergency surgery in patients on antiplatelet or anticoagulant therapy, and patients developing vasoplegia or septic shock. This focused narrative review critically appraises the current evidence base, examines the mechanistic rationale, and proposes a clinically applicable patient-selection framework to guide rational integration of CytoSorb® into high-risk cardiac surgical practice. Regulatory considerations including the recent United States Food and Drug Administration (FDA) De Novo denial for the related DrugSorb-ATR device are discussed in context.