Our understanding of the infection risks presented by tumour necrosis factor (TNF) antagonists has continued to evolve in the 10 years since these drugs were first introduced. Several recent studies have confirmed the increased risk of tuberculosis posed by TNF antibodies compared with soluble TNF receptor, particularly with regard to reactivation of latent infection. Structural and functional differences seem to account for this finding. This Review examines the potential relations between target specificity, stoichiometry, and binding kinetics of TNF blockers and their associated risk of infection. Clinical strategies for prevention and management of tuberculosis in patients treated with TNF blockers may be improved based on our evolving understanding of these differences.