A small minority of patients with asthma have severe disease that is refractory or poorly responsive and remain persistently symptomatic despite maximal inhaled therapy. These patients represent an important unmet clinical need as they suffer considerable morbidity and mortality and consume a disproportionately large amount of health care resource. Tumour necrosis factor- alpha (TNF-α) is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. Evidence is emerging to suggest that it may play an important role in severe, refractory disease. The development of novel TNF-α antagonist has allowed us to test the role of this cytokine in vivo. Early studies demonstrated an improvement in asthma quality-of-life, lung function, airway hyperresponsiveness (AHR) and a reduction in exacerbation frequency, in patients treated with anti-TNF-α therapy. However, there is marked heterogeneity in response suggesting that benefit is likely to be reserved to a small sub-group. This view is supported by the lack of efficacy in later large clinical trials, although subgroups of responders were identified. Importantly, concerns have been raised about the safety of anti-TNF-α therapies in severe asthma. Therefore, current evidence suggests that the risk of anti- TNF-α therapies outweighs benefit in severe asthma. In this review, we will discuss the role of TNF-α biology and its role in severe asthma, the clinical trials conducted so far and summarize the patents related to TNF-α and the antagonist drug therapies.