The management of rheumatoid arthritis has greatly improved in the past decade, owing to new treatment strategies and the introduction of agents that inhibit tumor necrosis factor (TNF). Unfortunately, a substantial proportion of patients will discontinue therapy with their first TNF inhibitor for various reasons (for example, non-response, loss of efficacy, or toxicity). Until recently, treatment options for these patients were limited and most rheumatologists chose to switch to treatment with an alternative TNF inhibitor. However, biologic agents with different modes of action have now become available. Hence, the dilemma now facing rheumatologists presented with patients who fail to respond to anti-TNF therapy is whether to switch to an alternative TNF inhibitor or to change to a biologic agent of a different drug class. This article discusses the evidence relating to these two options.