Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder designated with hyperplastic synovium, bone destruction and cartilage degradation. Current therapies involve targeting major cytokines and inflammatory mediators involved in RA to alleviate the pain and provide a temporary relief. Interleukin 21 (IL-21), a recently identified cytokine is known to possess a versatile role in modulating the cells of the RA synovium. Over the past decade, the pleiotropic role of IL-21 in RA pathogenesis has been implicated in several aspects. T helper 17 (Th17) and follicular T helper cells (Tfh), being the key immunomodulators of the RA synovium secrete high amounts of IL-21 during disease progression. Several studies have provided experimental evidences elucidating the multifaceted role of IL-21 in RA disease progression. IL-21 has the potential to activate T cells, B cells, monocytes/macrophages and synovial fibroblasts in RA pathogenesis through activation of JAK-STAT, MAPK and PI3K/Akt signaling pathways. Till date, therapies targeting Th17 cells and its inflammatory cytokines have been under investigation and are subjected to various clinical trials. This review showcases the role of IL-21 in RA pathogenesis and recent reports implicating its function in various immune cells, major signaling pathways, and in promoting osteoclastogenesis. © 2017 Wiley Periodicals, Inc.