Chronic pain is a debilitating condition that interferes with daily life, causing disability and depression.For chronic pain, especially of the neuropathic type, treatment options are few and ineffective.Our studies highlighted the importance of chronic inflammation in the microenvironment surrounding pain transmission pathway.An injury to the peripheral nerve triggers the recruitment of circulating monocytes and activation of resident macrophages in the damaged nerve.Two major phenotypes are identified: cytokine/chemokine expressing and phagocytic macrophages, which contribute to the peripheral sensitization through distinctive mechanisms.In the spinal cord where central sensory afferents terminate, the damaged nerve fibers release chemokine MCP-1 which is critical in inducing spinal glial activation.Both resident microglia and bone marrow-derived macrophages participate in the modulation of central sensitization in neuropathic pain.At the same time, the neuronal MCP-1 also alters the integrity of the blood spinal cord barrier, which allows the penetration of systemic inflammatory mediators and immune cells into the spinal cord.Our recent findings also demonstrated that anti-inflammatory treatment with pharmacological and genetic manipulation of immune/glial cell activities can alleviate neuropathic pain through restoring the neuron-glia-vascular homeostasis.The contribution of inflammation in the development and the persistence of pain after nerve injury challenge conventional concepts that focus on neural activity being solely responsible for the changes that drive neuropathic pain.This shift in our understanding provides an incredible opportunity to progress to a new therapeutic approach that will be beneficial for the millions of people suffering of neuropathic pain.