The article reviews the role of fever in immune regulation and its evolutionary significance. Fever, a response to infection that has been conserved for over 600 million years, is driven by both physiological and neuronal circuits and confers survival benefits during infection. The authors highlight the multifaceted role of interleukin-6 (IL-6), a pyrogenic cytokine, in both the induction of fever and the mobilization of lymphocytes to lymphoid organs. They also discuss emerging evidence that adrenergic signaling pathways associated with thermogenesis shape immune cell function. The review covers the induction of fever, the impact of febrile temperatures on innate and adaptive immunity, and the potential mechanisms underlying the spatial regulation of IL-6 during fever induction and lymphocyte trafficking. Additionally, it explores the role of thermogenesis and adrenergic signaling in immunity, suggesting that cold stress-induced norepinephrine production and β-adrenergic receptor signaling play crucial roles in immune modulation. The authors conclude by emphasizing the evolutionary conservation of the fever response and its protective role, while highlighting the need for further research to understand the temperature-sensing machinery and the spatial regulation of IL-6 during fever.The article reviews the role of fever in immune regulation and its evolutionary significance. Fever, a response to infection that has been conserved for over 600 million years, is driven by both physiological and neuronal circuits and confers survival benefits during infection. The authors highlight the multifaceted role of interleukin-6 (IL-6), a pyrogenic cytokine, in both the induction of fever and the mobilization of lymphocytes to lymphoid organs. They also discuss emerging evidence that adrenergic signaling pathways associated with thermogenesis shape immune cell function. The review covers the induction of fever, the impact of febrile temperatures on innate and adaptive immunity, and the potential mechanisms underlying the spatial regulation of IL-6 during fever induction and lymphocyte trafficking. Additionally, it explores the role of thermogenesis and adrenergic signaling in immunity, suggesting that cold stress-induced norepinephrine production and β-adrenergic receptor signaling play crucial roles in immune modulation. The authors conclude by emphasizing the evolutionary conservation of the fever response and its protective role, while highlighting the need for further research to understand the temperature-sensing machinery and the spatial regulation of IL-6 during fever.