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Background: Data from large cardiac surgery registries have been depicting a downward trend of mortality and morbidities in the last 20 years. However, despite decades of medical evolution, cardiac surgery and cardiopulmonary bypass still provoke a systemic inflammatory response, which occasionally leads to worsened outcome. This article seeks to outline the mechanism of the phenomenon., Methods: A thorough review of the literature has been performed. Criteria for considering studies for this non-systematic review were as follows: observational and interventional studies investigating the systemic inflammatory response to cardiac surgery, experimental studies describing relevant molecular mechanisms, and essential review studies pertinent to the topic., Results: The intrinsic variability of the inflammatory response to cardiac surgery, together with its heterogenous perception among clinicians, as well as the arduousness to early discriminate high-responder patients from those who will not develop a clinically relevant reaction, concurred to hitherto unconclusive randomized controlled trials. Furthermore, peremptory knowledge about the pathophysiology of maladaptive inflammation following heart surgery is still lacking., Conclusions: Systemic inflammation following cardiac surgery is a frequent entity that occasionally becomes clinically relevant. Specific genomic differences, age, and other preoperative factors influence the magnitude of the response, which elements display extreme redundancy and pleiotropism that the target of a single pathway cannot represent a silver bullet., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)