Immune cells play a critical role in both physiological and pathological pain, challenging the traditional view that pain is solely a neuronal phenomenon. Pain arises from interactions between immune and somatosensory systems, with immune cells contributing to the initiation, modulation, persistence, and resolution of various pain types. Immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. Innate and adaptive immune cells release ligands and mediators that influence pain mechanisms. The neuroimmune axis is an attractive target for pain treatment, but challenges such as objective pain quantification, sex differences in pain presentation, and immune system modulation must be addressed. Physiological pain alerts us to danger, while pathological pain, such as that following inflammation or nerve injury, can be debilitating. Nociceptive pain is triggered by high-threshold sensory neurons, while inflammatory pain hypersensitivity is influenced by immune mediators. Neuropathic pain, resulting from nervous system damage, is maladaptive and can persist even without ongoing inflammation. Nociplastic pain, occurring without noxious stimuli, is linked to dysfunctional nociceptive systems. Immune cells, including macrophages, dendritic cells, and T cells, regulate pain through various mechanisms. For example, macrophages can both promote and suppress pain, while T cells influence pain hypersensitivity. Inflammatory pain is driven by immune mediators like cytokines, chemokines, and antibodies, which act on nociceptors. Neuropathic pain involves immune cells in the peripheral nerves and spinal cord, contributing to pain through altered ion channel function and neuronal excitability. The neuroimmune axis is a promising target for pain treatment, but challenges remain in developing effective immunotherapies. Sex differences in pain perception and immune responses must be considered. Immune modulation can lead to adverse outcomes, highlighting the need for careful targeting. Advances in preclinical pain metrics, such as machine learning-based assessments, are improving the evaluation of neuroimmune-based therapies. Overall, the immune system is integral to pain mechanisms, and understanding its role is essential for developing effective and safe pain treatments.Immune cells play a critical role in both physiological and pathological pain, challenging the traditional view that pain is solely a neuronal phenomenon. Pain arises from interactions between immune and somatosensory systems, with immune cells contributing to the initiation, modulation, persistence, and resolution of various pain types. Immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. Innate and adaptive immune cells release ligands and mediators that influence pain mechanisms. The neuroimmune axis is an attractive target for pain treatment, but challenges such as objective pain quantification, sex differences in pain presentation, and immune system modulation must be addressed. Physiological pain alerts us to danger, while pathological pain, such as that following inflammation or nerve injury, can be debilitating. Nociceptive pain is triggered by high-threshold sensory neurons, while inflammatory pain hypersensitivity is influenced by immune mediators. Neuropathic pain, resulting from nervous system damage, is maladaptive and can persist even without ongoing inflammation. Nociplastic pain, occurring without noxious stimuli, is linked to dysfunctional nociceptive systems. Immune cells, including macrophages, dendritic cells, and T cells, regulate pain through various mechanisms. For example, macrophages can both promote and suppress pain, while T cells influence pain hypersensitivity. Inflammatory pain is driven by immune mediators like cytokines, chemokines, and antibodies, which act on nociceptors. Neuropathic pain involves immune cells in the peripheral nerves and spinal cord, contributing to pain through altered ion channel function and neuronal excitability. The neuroimmune axis is a promising target for pain treatment, but challenges remain in developing effective immunotherapies. Sex differences in pain perception and immune responses must be considered. Immune modulation can lead to adverse outcomes, highlighting the need for careful targeting. Advances in preclinical pain metrics, such as machine learning-based assessments, are improving the evaluation of neuroimmune-based therapies. Overall, the immune system is integral to pain mechanisms, and understanding its role is essential for developing effective and safe pain treatments.