The article by David C. Fajgenbaum, M.D., and Carl H. June, M.D., discusses the critical role of an effective host immune response and the devastating effects of immune dysregulation, particularly in the context of the SARS-CoV-2 pandemic. The term "cytokine storm" refers to life-threatening systemic inflammatory syndromes 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. The authors highlight the historical context of cytokine storms, including their association with influenza-like syndromes, sepsis, and immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy. They emphasize the lack of a widely accepted definition for cytokine storms and the challenges in distinguishing them from appropriate inflammatory responses. The clinical features of cytokine storms include constitutional symptoms, systemic inflammation, and multiorgan dysfunction, often leading to multiorgan failure. Laboratory findings are variable but typically include elevated nonspecific markers of inflammation, hypertriglyceridemia, and blood count abnormalities. The authors propose a three-pronged approach to evaluating cytokine storms: identifying the underlying disorder, establishing severity, and determining the clinical trajectory. They also discuss the pathophysiological mechanisms of cytokine storms, involving immune hyperactivation through inappropriate or ineffective triggering, exaggerated effector responses, and failure to terminate homeostasis. The article further explores the cell types involved in cytokine storms, including innate and adaptive immune cells, and the key cytokines such as interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18. It highlights the role of these cytokines in driving the hyperinflammatory response and their potential therapeutic targets. The authors also discuss iatrogenic, pathogen-induced, monogenic, autoimmune, and COVID-19-associated cytokine storms, emphasizing the complexity of their causes and treatments. They conclude by addressing the challenges in treating cytokine storms, particularly in the context of COVID-19, and the need for targeted therapies that can effectively manage the immune response without impairing the body's defense against pathogens.The article by David C. Fajgenbaum, M.D., and Carl H. June, M.D., discusses the critical role of an effective host immune response and the devastating effects of immune dysregulation, particularly in the context of the SARS-CoV-2 pandemic. The term "cytokine storm" refers to life-threatening systemic inflammatory syndromes 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. The authors highlight the historical context of cytokine storms, including their association with influenza-like syndromes, sepsis, and immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy. They emphasize the lack of a widely accepted definition for cytokine storms and the challenges in distinguishing them from appropriate inflammatory responses. The clinical features of cytokine storms include constitutional symptoms, systemic inflammation, and multiorgan dysfunction, often leading to multiorgan failure. Laboratory findings are variable but typically include elevated nonspecific markers of inflammation, hypertriglyceridemia, and blood count abnormalities. The authors propose a three-pronged approach to evaluating cytokine storms: identifying the underlying disorder, establishing severity, and determining the clinical trajectory. They also discuss the pathophysiological mechanisms of cytokine storms, involving immune hyperactivation through inappropriate or ineffective triggering, exaggerated effector responses, and failure to terminate homeostasis. The article further explores the cell types involved in cytokine storms, including innate and adaptive immune cells, and the key cytokines such as interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18. It highlights the role of these cytokines in driving the hyperinflammatory response and their potential therapeutic targets. The authors also discuss iatrogenic, pathogen-induced, monogenic, autoimmune, and COVID-19-associated cytokine storms, emphasizing the complexity of their causes and treatments. They conclude by addressing the challenges in treating cytokine storms, particularly in the context of COVID-19, and the need for targeted therapies that can effectively manage the immune response without impairing the body's defense against pathogens.