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The Identification of key players of inflammation and pathologic immune response in rheumatoid arthritis (RA) has resulted in the development of novel therapeutic strategies revolutionising the treatment of disease. However, these new therapeutics only indirectly affect the mesenchymal compartment of the inflamed synovium and, in particular, the specific phenotype of activated fibroblast-like cells. These cells have been demonstrated to trigger not only the progressive destruction of articular cartilage and bone but also the switch from acute to chronic inflammation. Therefore, targeting of this population of fibroblast-like cells may provide interesting opportunities to go beyond the mere inhibition of inflammation and to interfere with key disease processes in RA. This review summarises our current knowledge on the role of fibroblast-like cells in RA and points to potentials ways of modulating their disease-specific activation.