Pathogenic processes that underlie the development and progression of systemic sclerosis (SSc) are being defined in preclinical, clinical and genetic studies. Important evidence of interplay between the vasculature, connective tissue and specialized epithelial structures is emerging, and abnormalities of both the innate and adaptive immune systems have been identified. In this context, information regarding pivotal mediators, pathways or cell types that could be targets for therapeutic intervention, and that might offer potential for true disease modification, is accruing. Precedent for the regression of some aspects of the pathology has been set in clinical studies showing that potential exists to improve tissue structure and function as well as to prevent disease progression. This article reviews the concept of targeted therapies and considers potential pathways and processes that might be attenuated by therapeutic intervention in SSc. As well as improving outcomes, such approaches will undoubtedly provide information about pathogenesis. The concept of translational medicine is especially relevant in SSc, and we anticipate that the elusive goal of an effective antifibrotic treatment will emerge from one of the several clinical trials currently underway or planned in this disease. Therapeutic advances in SSc would have implications and potential beyond autoimmune rheumatic diseases.