Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive articular damage. Activated cells of the synovium produce pro-inflammatory and matrix-degrading effector molecules, which maintain the inflammation and lead to the destruction of the involved joints. In addition to macrophages and T- and B-cells, fibroblast-like synoviocytes must be considered key cells in driving the pathological processes. They can be distinguished by their transformed-appearing phenotype and their invasion into adjacent cartilage and bone. Synovial activation is driven by pro-inflammatory cytokines as well as cytokine independent pathways including endogenous retroviral elements and Toll-like receptors (TLR). These pathways are connected by a complex network of autocrine and paracrine acting factors. Another feature of RA synovium is hyperplasia of the lining layer, which results from increased proliferation and decreased apoptosis of synovial fibroblasts. Thanks to new techniques in basic research, novel insights into the cellular and molecular mechanisms of the pathogenesis of RA were gained and led to the development of new, specific therapeutic strategies.