Rheumatoid arthritis (RA) is a chronic autoimmune disease of still unknown etiology that results in characteristic destructive changes of the joints. Research of the past years has demonstrated that synovial fibroblasts play a central role in the initiation and perpetuation of these destructive changes. Stimulation of the synovial fibroblasts through complex and interacting intracellular signaling pathways results in a stable activation that is maintain even without continuous stimulation by inflammatory cells and their mediators. The pathological attachment to articular cartilage, increased secretion of matrix degrading enzymes and alterations in programmed cell death are main characteristics of synovial fibroblasts from patients with RA and result in the progressive destruction of articular structures. The permanent activation of a number of intracellular signaling pathways constitutes the underlying responsible mechanism for the activation of synovial fibroblasts in RA. These signaling pathways do not only show a high degree of complexity, but are also interconnected in multiple ways. This article summarizes recent findings on the activation of intracellular signaling pathways in fibroblasts and points to potential targets for novel therapeutic strategies.