Identification of interleukin-17 (IL-17) as a powerful proinflammatory cytokine and the recent recognition of a T-helper cell subset that secretes it have focused attention on the role of IL-17 and Th17 cells in rheumatoid arthritis (RA) and other immune-mediated diseases. While understanding of its role in RA is still evolving, evidence from both animal models and human systems provides a compelling rationale for therapeutic targeting of IL-17 in RA. Both direct and indirect approaches to accomplish this are feasible. Mechanistic studies in the context of clinical trials will be required to understand why some strategies may be preferable from the perspectives of efficacy and safety.