Success achieved so far in the blockade of tumor necrosis factor and interleukin (IL)-1 in rheumatoid arthritis exemplifies the feasibility and potential therapeutic application of antagonizing cytokine signaling. Despite these advances, there remains a considerable unmet clinical need in this field. A number of preclinical development programs are ongoing to target a variety of cytokines that are central to immune regulation and tissue-matrix destruction in rheumatoid arthritis. Evidence indicates that IL-6 antagonists might represents a useful approach and preliminary data similarly identify IL-15 as an intriguing target. Numerous additional cytokines are under investigation at the preclinical stage, including IL-12-IL-23, IL-17 and IL-18. As therapeutic goals move from disease control towards remission induction, development of the capacity for cytokine targeting to modify the underlying immune dysregulation remains a major priority.