Cytokines such as tumor necrosis factor (TNF) are expressed at high levels in rheumatoid joint tissue, where they contribute significantly to inflammation and articular destruction. TNF was the first cytokine to be fully validated as a therapeutic target for rheumatoid arthritis (RA). In nearly a decade since anti-TNF agents—such as infliximab, etanercept and adalimumab—were launched as the first biologic therapies to be licensed for RA, much has been learnt about how and when in the disease course this class of drug can be used to achieve optimal therapeutic benefit. Other cytokine targets, such as interleukin (IL)-6 or IL-1, have also been validated and several are in the process of being tested. However, TNF is likely to remain the preferred target of first-line biologic therapy for the foreseeable future as, in populations with active RA despite ongoing, nonbiologic, DMARD therapy, biologic inhibition of either IL-6 or IL-1 demonstrates no obviously superior outcomes to TNF blockade. Furthermore, new approaches to blockade of signaling mediated by bioactive TNF might have the potential to generate higher-magnitude clinical responses than are currently elicited.