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Pain is an unpleasant sensation associated with injury, inflammation, and infection. It has been demonstrated that communication between immune cells and neurons plays a vital role in pain and pain-related diseases (e.g. multiple sclerosis, osteoarthritis, irritable bowel syndrome). Growing data from preclinical and clinical studies have established that the bilateral regulations between peripheral immune cells and nociceptive neurons could be beneficial or detrimental for the development of pain and immune defense. We here review the mechanisms underlying neuroimmune crosstalk between circulating immune cells (e.g. macrophages, T cells, mast cells, neutrophils, monocytes) and nociceptors in the peripheral nervous system and the spinal cord. Deciphering the mechanisms by which neuroimmune interaction integrates neuronal inputs and immune responses helps to understand the pathogenesis of pain-related diseases and develop effective medications.