Ischemia and reperfusion injury, characterized by an initial restriction of blood supply followed by the restoration of perfusion, is a significant contributor to morbidity and mortality in various pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease, and sleep apnea. The imbalance in metabolic supply and demand during ischemia leads to profound tissue hypoxia and microvascular dysfunction, which, when reperfusion occurs, exacerbates tissue injury and inflammation. Recent advances in understanding the molecular and immunological mechanisms of ischemia and reperfusion have led to the development of innovative therapeutic strategies. These include targeting innate and adaptive immune responses, inhibiting cell death programs, and modulating metabolic pathways to enhance ischemia tolerance. Therapeutic approaches such as ischemic preconditioning, postconditioning, and remote conditioning, as well as the use of therapeutic gases like hydrogen, nitric oxide, and carbon monoxide, show promise in reducing tissue injury. Additionally, targeting microRNAs and adenosine receptors offers potential for new treatments. Despite these advancements, further mechanistic insights and clinical trials are needed to fully realize the therapeutic potential of these approaches.Ischemia and reperfusion injury, characterized by an initial restriction of blood supply followed by the restoration of perfusion, is a significant contributor to morbidity and mortality in various pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease, and sleep apnea. The imbalance in metabolic supply and demand during ischemia leads to profound tissue hypoxia and microvascular dysfunction, which, when reperfusion occurs, exacerbates tissue injury and inflammation. Recent advances in understanding the molecular and immunological mechanisms of ischemia and reperfusion have led to the development of innovative therapeutic strategies. These include targeting innate and adaptive immune responses, inhibiting cell death programs, and modulating metabolic pathways to enhance ischemia tolerance. Therapeutic approaches such as ischemic preconditioning, postconditioning, and remote conditioning, as well as the use of therapeutic gases like hydrogen, nitric oxide, and carbon monoxide, show promise in reducing tissue injury. Additionally, targeting microRNAs and adenosine receptors offers potential for new treatments. Despite these advancements, further mechanistic insights and clinical trials are needed to fully realize the therapeutic potential of these approaches.