The cause of low back pain and the pathophysiology of lumbar pain and sciatica have recently been reconsidered basing on current knowledge on cellular and molecular mediators of inflammation. Several cytokines have been considered as potential therapeutic targets to contrast sciatica in patients with disc herniation, and supportive studies suggest a leading role of TNF-α in this contest: therefore, clinical trials have tested TNF-α inhibitors in the clinical setting of the patient with radicular pain secondary to an herniated disc. The current review deals with the autoimmune theory of disc herniation and its role in determining radiculopathy and neuropathic pain. It also reports the recent evidences that led to the introduction of anti-TNF-α drugs into the clinical setting as a biological therapy for radiculopathy and disc herniation. Targeting the TNF-α pathway has demonstrated controversial effects in the tested study population and available results only report a short-term follow-up. More confirmatory studies in terms of long-term clinical results, complications, more effective route of administration and cost-effective analysis are required to establish the real role of this biological therapy in the treatment of patients with disc herniation and neuropathy.