Cytokine storm is a life-threatening systemic inflammatory condition characterized by elevated levels of circulating cytokines and immune-cell hyperactivation, which can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders. This review discusses the pathophysiology, clinical features, and management of cytokine storm, including iatrogenic, pathogen-induced, neoplastic, and monogenic causes. The authors propose a unifying definition of cytokine storm based on elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction. Cytokine storm can occur due to inappropriate immune recognition, exaggerated effector responses, or failure to resolve the immune response. The clinical features include fever, fatigue, rash, diarrhea, arthralgia, myalgia, and neurologic toxicity. Laboratory findings include elevated inflammatory markers such as C-reactive protein (CRP), ferritin, and D-dimer. The management of cytokine storm involves identifying the underlying cause, assessing severity, and using immunomodulatory therapies such as monoclonal antibodies targeting interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-gamma (IFN-γ). Cytokine storm can be caused by various factors, including CAR T-cell therapy, sepsis, viral infections, and genetic disorders. In the context of SARS-CoV-2 infection, cytokine storm is a significant complication that can lead to multiorgan failure and death. The review highlights the importance of recognizing cytokine storm for its prognostic and therapeutic implications, and emphasizes the need for further research to develop effective treatments.Cytokine storm is a life-threatening systemic inflammatory condition characterized by elevated levels of circulating cytokines and immune-cell hyperactivation, which can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders. This review discusses the pathophysiology, clinical features, and management of cytokine storm, including iatrogenic, pathogen-induced, neoplastic, and monogenic causes. The authors propose a unifying definition of cytokine storm based on elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction. Cytokine storm can occur due to inappropriate immune recognition, exaggerated effector responses, or failure to resolve the immune response. The clinical features include fever, fatigue, rash, diarrhea, arthralgia, myalgia, and neurologic toxicity. Laboratory findings include elevated inflammatory markers such as C-reactive protein (CRP), ferritin, and D-dimer. The management of cytokine storm involves identifying the underlying cause, assessing severity, and using immunomodulatory therapies such as monoclonal antibodies targeting interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-gamma (IFN-γ). Cytokine storm can be caused by various factors, including CAR T-cell therapy, sepsis, viral infections, and genetic disorders. In the context of SARS-CoV-2 infection, cytokine storm is a significant complication that can lead to multiorgan failure and death. The review highlights the importance of recognizing cytokine storm for its prognostic and therapeutic implications, and emphasizes the need for further research to develop effective treatments.