Systemic sclerosis (SSc), also known as scleroderma, is a complex connective tissue disease that is associated with a high mortality and is challenging to treat because of its clinical heterogeneity and a lack of effective antifibrotic therapies. SSc has vascular, immunologic and fibrotic components that are pathologically interconnected. A growing understanding of the molecular and cellular mechanisms that underlie SSc pathogenesis provides logical and novel approaches to treatment. At present most therapies are organ-based. Vascular and inflammatory components of the disease can also be treated, but effective antifibrotic therapies are lacking. A number of key molecular mediators have the potential to alter immune-cell, vascular and fibrotic processes and these mediators, which include transforming growth factor-beta isoforms, endothelin-1, connective-tissue growth factor, chemokines and members of the interleukin family, are attractive targets for therapeutic modulation. Key mediators can be blocked using antibodies, soluble receptors, endogenous inhibitors or small-molecule antagonists of ligands, receptors or signaling intermediates. Overall, this is an exciting time for new therapies in SSc and advances are being made in synchrony with an improved understanding of the molecular and biochemical basis of the disease.