Strong evidence suggests that TNF- may be among the chemical factors involved in disk-related sciatica. TNF- is involved in the genesis of nerve pain in animal models and may promote pain-signal production from nerve roots previously subjected to mechanical deformation. In animal experiments, TNF- has been identified in nucleus pulposus and Schwann cells. Local production of endogenous TNF- may occur early in the pathogenic process. Exposure to exogenous TNF- induces electrophysiological, histological, and behavioral changes similar to those seen after exposure to nucleus pulposus, and these changes are more severe when mechanical compression is applied concomitantly. TNF- antagonists diminish or abolish abnormalities in animal models. Other cytokines may be involved also, as suggested by the potent inhibitory effects of compounds such as doxycycline. Two open-label studies in humans suggest dramatic efficacy of TNF- antagonists in alleviating disk-related sciatica. In contrast, the results of the only controlled study available to date do not support a therapeutic effect of TNF- antagonists. Thus, whether TNF- antagonist therapy is warranted in patients with disk-related sciatica remains an open question, and further randomized controlled studies are needed.