The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal pathways. The neuroendocrine stress response, the sympathetic nervous system, and the parasympathetic nervous system generally inhibit innate immune responses, while the peripheral nervous system amplifies local innate immune responses. These systems work together to activate and amplify local inflammatory responses to contain or eliminate pathogens and then terminate inflammation to restore homeostasis. The review discusses the regulatory mechanisms and evidence that the CNS is integral to acute-phase inflammatory responses to pathogens as part of the innate immune system. The local acute-phase inflammatory response is characterized by redness, pain, and heat, all of which have neural origins. Similarly, the systemic acute-phase response involves key neural elements such as fever and the activation of the central hormonal-stress response. Immune mediators and cytokines released by the innate immune system activate neural responses that amplify local immune responses and trigger systemic neuroendocrine and regional neural responses to return the system to a resting state. However, prolonged or inappropriate counter-regulatory responses from the CNS can lead to excess inflammation or uncontrolled infection, potentially causing pathological and lethal effects. The review also covers the general principles and areas of controversy in the interaction between the nervous system and the innate immune system, including the role of G-protein-coupled receptors and the effects of neural factors on immune responses.The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal pathways. The neuroendocrine stress response, the sympathetic nervous system, and the parasympathetic nervous system generally inhibit innate immune responses, while the peripheral nervous system amplifies local innate immune responses. These systems work together to activate and amplify local inflammatory responses to contain or eliminate pathogens and then terminate inflammation to restore homeostasis. The review discusses the regulatory mechanisms and evidence that the CNS is integral to acute-phase inflammatory responses to pathogens as part of the innate immune system. The local acute-phase inflammatory response is characterized by redness, pain, and heat, all of which have neural origins. Similarly, the systemic acute-phase response involves key neural elements such as fever and the activation of the central hormonal-stress response. Immune mediators and cytokines released by the innate immune system activate neural responses that amplify local immune responses and trigger systemic neuroendocrine and regional neural responses to return the system to a resting state. However, prolonged or inappropriate counter-regulatory responses from the CNS can lead to excess inflammation or uncontrolled infection, potentially causing pathological and lethal effects. The review also covers the general principles and areas of controversy in the interaction between the nervous system and the innate immune system, including the role of G-protein-coupled receptors and the effects of neural factors on immune responses.