The pathogenesis of systemic sclerosis (SSc) is complex and appears to involve endothelium, epithelium, fibroblasts and immunological mediators, resulting in dysregulated vascular remodelling and ultimately vasculopathy. Endothelial cell injury is an early and probably initiating event, but the precise aethyology remains unclear. Vascular damage and tissue fibrosis are widespread in SSc and largely account for the protean clinical manifestations and substantial morbidity and mortality. Current therapies are primarily immunomodulatory in nature. Effective therapy will require directly targeting the fibrotic process and will necessitate an improved understanding of the roles of individual cell types and their products in the development of fibrosis.