Fibrosis affects organs such as the skin, liver, kidney and lung and is a cause of significant morbidity. There is no therapy for fibrosis. Recent significant molecular insights into the signaling underlying the fibrosis in the autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc) have been made. Transforming growth factor beta (TGFbeta) signaling is a major contributor to fibrogenesis, including in SSc. However, it is now appreciated that TGFbeta-dependent and TGFbeta-independent mechanisms play key roles in the pathological fibrosis in SSc. In particular the potent pro-fibrotic proteins endothelin-1 (ET-1) and CCN2 (connective tissue growth factor, CTGF) are believed to play an essential role in this process. This review summarizes these recent crucial observations.