Neuropathic pain is a debilitating chronic pain and represents a major clinical challenge. The molecular and cellular mechanisms underlying its development and maintenance are not fully understood but involve abnormal excitability in the dorsal horn of the spinal cord. A growing body of evidence has shown that this aberrant excitability may be a consequence not merely of changes in neurons but rather of multiple alterations in microglia, which are resident macrophages in the central nervous system. This review highlights recent advances in our understanding of the mechanisms that underlie neuropathic pain caused by peripheral nerve injury, with a specific focus on purinergic signaling in spinal cord microglia. This provides convincing evidence for a crucial role for microglial purinergic signaling in the pathogenesis of neuropathic pain, and P2 receptors may be potential therapeutic targets for managing neuropathic pain. © 2016 Wiley Periodicals, Inc.