Microglial cells appear to play a vital role in the initiation of certain neuropathic pain states. In order to initiate neuropathic pain, microglia need to be activated. Microglia activation in the spinal cord involves both hypertrophy as well as hyperplasia, progressing through a hypertrophic morphology, with thickened and retracted processes (observed within the first 24 hours after nerve injury), and an increase in cell number (observed around 2–3 days after nerve injury). There seems to be at least 5 major paths to activate microglia. These 5 pathways will be discussed and are identified by their main signaling mediator and/or receptor which include fractalkine, interferon-gamma, monocyte chemoattractant protein-1, TLR4, and P2X4. Thus, one or more of these mediators/pathways which lead to microglial activation might contribute to neuropathic pain. A greater appreciation of the roles of various mediators/paths which activate microglia might help lead to future novel therapeutic targets in efforts to ameliorate severe symptoms of neuropathic pain. Key words: microglial cells, glia, C-fiber nociceptors, neuropathic pain, hypertrophy, hyperplasia