The introduction of TNF inhibitors into the clinic for the treatment of patients with rheumatoid arthritis and other systemic inflammatory conditions has revolutionised the approach to these diseases. Despite the substantial efficacy of these agents, a subset of patients either does not respond or has a suboptimal clinical response. Defining what constitutes 'failure' of this type of therapy is important in both clinical research and practice. For patients who fail to respond to TNF inhibitors, a number of promising avenues targeting other aspects of the immune system are under study, and may be brought to the clinic in the near future.