Over the past 20 years, the hypothesis that inflammation was an important component of the pathophysiology of sciatica has slowly emerged. Numerous studies in a variety of animal models have been published to sustain this hypothesis, but it is only recently that we were able to produce the first evidence that tumor necrosis factor (TNF)-α could be an important mediator in human sciatica. We were able to demonstrate that there was a higher concentration of TNF-α in the vicinity of the inflamed nerve root in sciatica cases than in controls with other types of back pain. On the other hand, the results from a randomized, double-blind, placebo-controlled trial confirmed the initial impression from a pilot study of the efficacy of TNF-α inhibitors in the treatment of acute severe sciatica. However, the effect was more limited than expected and, both at the bench and at the bedside, clues are accumulating to suggest that other alternatives to systemically delivered TNF-α inhibitors should now be explored.