A variety of mechanisms may generate pain resulting from injury to the peripheral nervous system. None of these mechanisms is disease-specific, and several different pain mechanisms may be simultaneously present in any one patient, independent of diagnosis. Diagnosis of neuropathic pain is often easily made from information gathered on neurologic examination and from patient history. Evidence of sensory disturbances elicited on examination combined with laboratory tests confirming injury to peripheral nerve establishes the diagnosis of neuropathic pain. Although treatment of neuropathic pain may be difficult, optimum treatment can be achieved if the neurologist has a complete understanding of the therapeutic options, the mainstay of which is pharmacotherapy. Selection of an appropriate pharmacologic agent is by trial and error since individual responses to different agents, doses, and serum levels are highly variable. An adequate trial for each agent tried is key to pharmacologic treatment of neuropathic pain. Tricyclic antidepressants are first-line agents, although other drugs, including anticonvulsants, local anesthetic antiarrhythmics, clonidine, opioids, and certain topical agents, also offer pain relief in some patient populations. The novel antidepressants venlafaxine and nefazodone are potentially useful new drugs that are better tolerated than tricyclic antidepressants.