Tumour necrosis factor has been found to play a central role in the pathogenesis of rheumatoid arthritis, leading to development of novel drug therapies that neutralise the deleterious effects of this cytokine. This new concept of immunological treatment of rheumatoid arthritis has yielded successful results. Several studies have shown that the 3 available TNF-α blockers: infliximab, etanercept and adalimumab, though differ in structure and mechanism of action, have provided similar positive benefits both in clinical improvement and in slowing down the progression of radiographic damage. However, despite these successes, a significant proportion of patients with RA as well as other inflammatory conditions do not show definite improvement with this therapy. Therefore, the next major advance might be the identification of predictors of treatment response, such as genetic polymorphism that may enhance the efficiency by which these expensive therapies are used in clinical practice. This article discusses the positive response of TNF-α therapy as evidenced from the several clinical trials published, the differences between the different TNF-α blocking agents, the parameters useful in the identification of non-responders and the way to manage such patients.