Cytokine release syndrome (CRS) is a systemic inflammatory response that can occur as a side effect of various immunotherapies, particularly those targeting T cells. This review provides a comprehensive overview of the mechanisms, risk factors, clinical presentation, differential diagnoses, and prognostic factors of CRS. It also offers practical guidance on managing CRS. CRS can range from mild flu-like symptoms to severe life-threatening manifestations, including hypotension, high fever, multi-organ failure, and neurotoxicity. The severity of CRS is influenced by factors such as the type of therapy, underlying disease, and patient characteristics. Common differential diagnoses include tumor lysis syndrome, sepsis, and hemophagocytic lymphohistiocytosis (HLH). The pathophysiology of CRS involves the activation of bystander immune cells and endothelial cells, leading to a cytokine storm. Key cytokines involved include IL-6, IL-10, and interferon (IFN)-γ. Treatment strategies for CRS include symptom management, empirical antibiotic therapy, and the use of monoclonal antibodies targeting IL-6, such as tocilizumab. The management of CRS is evolving, and future research is needed to improve diagnostic tools and therapeutic options.Cytokine release syndrome (CRS) is a systemic inflammatory response that can occur as a side effect of various immunotherapies, particularly those targeting T cells. This review provides a comprehensive overview of the mechanisms, risk factors, clinical presentation, differential diagnoses, and prognostic factors of CRS. It also offers practical guidance on managing CRS. CRS can range from mild flu-like symptoms to severe life-threatening manifestations, including hypotension, high fever, multi-organ failure, and neurotoxicity. The severity of CRS is influenced by factors such as the type of therapy, underlying disease, and patient characteristics. Common differential diagnoses include tumor lysis syndrome, sepsis, and hemophagocytic lymphohistiocytosis (HLH). The pathophysiology of CRS involves the activation of bystander immune cells and endothelial cells, leading to a cytokine storm. Key cytokines involved include IL-6, IL-10, and interferon (IFN)-γ. Treatment strategies for CRS include symptom management, empirical antibiotic therapy, and the use of monoclonal antibodies targeting IL-6, such as tocilizumab. The management of CRS is evolving, and future research is needed to improve diagnostic tools and therapeutic options.