Ischemia-reperfusion injury (IRI) is a critical medical condition characterized by severe clinical manifestations such as myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. This review article focuses on the basic pathophysiology of IRI, particularly the involvement of reactive oxygen species (ROS) and cell death pathways. The NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are highlighted for their roles in generating ROS. When blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury can result in apoptosis, autophagy, necrosis, and necroptosis. The article discusses the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes and highlights the interlinked signaling pathways of cell death, which offer new targets for therapeutic approaches. Treatment strategies for IRI are also reviewed, emphasizing the importance of understanding the pathophysiology to develop novel therapeutic interventions.Ischemia-reperfusion injury (IRI) is a critical medical condition characterized by severe clinical manifestations such as myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. This review article focuses on the basic pathophysiology of IRI, particularly the involvement of reactive oxygen species (ROS) and cell death pathways. The NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are highlighted for their roles in generating ROS. When blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury can result in apoptosis, autophagy, necrosis, and necroptosis. The article discusses the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes and highlights the interlinked signaling pathways of cell death, which offer new targets for therapeutic approaches. Treatment strategies for IRI are also reviewed, emphasizing the importance of understanding the pathophysiology to develop novel therapeutic interventions.