Tumor necrosis factor (TNF)-α is a proinflammatory cytokine. Blocking TNF-α has been demonstrated to be effective in various diseases, including both rheumatoid and psoriatic arthritis. There is evidence to show that levels of TNF-α are elevated in patients with severe asthma. TNF-α is involved in the initiation and perpetuation of the inflammatory process, epithelial damage and remodeling, and mucin hypersecretion. Furthermore, TNF-α polymorphism has also been reported in the asthmatic population. Based on the necessity for alternative treatments for asthmatics with severe disease and those who are particularly resistant to conventional asthma therapy, it has been shown that molecules targeted at blocking the effects of TNF-α probably constitute a considerable advance in the management of these difficult patients. This review focuses on the evidence of TNF-α axis upregulation in severe corticosteroid-refractory asthma, as well as the role of TNF-α inhibition and the adverse effects of treatment.