Neuroinflammation is a proinflammatory cytokine-mediated process that can be provoked by systemic tissue injury but it is most often associated with direct injury to the nervous system. It involves neural-immune interactions that activate immune cells, glial cells and neurons and can lead to the debilitating pain state known as neuropathic pain. It occurs most commonly with injury to peripheral nerves and involves axonal injury with Wallerian degeneration mediated by hematogenous macrophages. Therapy is problematic but new trials with anti-cytokine agents, cytokine receptor antibodies, cytokine-signaling inhibitors, and glial and neuron stabilizers provide hope for future success in treating neuropathic pain.