Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells of synovial joints that have been recognized to play an increasingly important role in the pathogenesis of rheumatoid arthritis (RA). Activation of FLS in the setting of RA leads to the production of a broad array of cell surface and soluble mediators that help to recruit, retain, and activate both cells of the immune system and resident joint cells, leading to the promotion of ongoing inflammation and tissue destruction. The ability of FLS to stimulate both inflammation and tissue damage suggests that this cell type may be a unique target for the treatment of inflammatory arthritis. Greater understanding of how FLS are activated and how they interact with other cells in the RA synovium may provide insights that allow development of novel agents for RA therapy.