Finding effective treatments for patients with systemic sclerosis (SSc) remains one of the final frontiers in therapeutic discovery. Although remarkable progress has been made in the symptomatic treatment of various organ system manifestations, little is available that treats the underlying disease process. SSc patients do not respond to many of the medications that provide benefit in related diseases, such as systemic lupus erythematosus, polymyositis and chronic graft-versus-host disease. Current research has not even clarified whether the complex pathogenesis starts primarily in vascular, immunological or connective tissues. Herein are discussed selected emerging therapeutics and therapeutic approaches designed to target the underlying immunological and fibrotic disease processes. Distinctive fibrotic features and data from translational research consistently place transforming growth factor-beta (TGFbeta) as a central mediator in SSc. The discovery of agents targeting TGFbeta, its activation or its intracellular signaling suggest that TGFbeta pathway inhibitors efficacious for the treatment of SSc may soon be identified. IL-4 and IL-13 are other fibrotic mediators produced during immune activation that might be targeted for SSc therapy, and therapeutics targeting these interleukins are also being developed. Immune dysregulation, leading to overproduction of these or other fibrotic mediators might respond to currently available immunosuppressives: mycophenolate, cyclosporine, tacrolimus or sirolimus, alone or in combination. Nucleic acid-containing immune complexes may also contribute to toll-like receptor mediated immune dysregulation in SSc, suggesting that agents targeting the innate immune system may ameliorate SSc. Thus, the complexity of SSc pathogenesis provides a plethora of targets for urgently needed new therapies.