The chapter discusses the role of immune cells in both physiological and pathological pain. Physiological pain serves as a warning system to avoid harmful stimuli, while pathological pain, such as chronic pain following inflammation or nervous system injury, can be debilitating. Immune cells, including both innate and adaptive immune cells, play a crucial role in mediating pain by interacting with somatosensory neurons. These interactions can occur in the skin, nerve, dorsal root ganglia, and spinal cord. Innate immune cells like macrophages and neutrophils, and adaptive immune cells like T and B cells, contribute to the initiation, modulation, persistence, or resolution of various types of pain. The chapter highlights recent findings on how these immune cells release ligands and mediators to influence pain pathways. It also emphasizes the potential of targeting the neuroimmune axis as a therapeutic approach for pain management, despite challenges such as quantifying pain preclinically and understanding sex differences in pain presentation. The chapter concludes by discussing the need for more effective and safer pain treatments that consider the complex interactions between the immune and nervous systems.The chapter discusses the role of immune cells in both physiological and pathological pain. Physiological pain serves as a warning system to avoid harmful stimuli, while pathological pain, such as chronic pain following inflammation or nervous system injury, can be debilitating. Immune cells, including both innate and adaptive immune cells, play a crucial role in mediating pain by interacting with somatosensory neurons. These interactions can occur in the skin, nerve, dorsal root ganglia, and spinal cord. Innate immune cells like macrophages and neutrophils, and adaptive immune cells like T and B cells, contribute to the initiation, modulation, persistence, or resolution of various types of pain. The chapter highlights recent findings on how these immune cells release ligands and mediators to influence pain pathways. It also emphasizes the potential of targeting the neuroimmune axis as a therapeutic approach for pain management, despite challenges such as quantifying pain preclinically and understanding sex differences in pain presentation. The chapter concludes by discussing the need for more effective and safer pain treatments that consider the complex interactions between the immune and nervous systems.