Purpose of review: Systemic sclerosis is a disease characterized by vascular and skin changes associated with activation of fibroblasts and increased synthesis of matrix components. These abnormalities lead to fibrosis and impaired function of internal organs such as the lung, kidney, and gastrointestinal tract. Recent evidence suggests that although activation of cells in and around the blood vessels and in the skin occurs in systemic sclerosis, injury to the vascular endothelium and defective apoptosis of skin fibroblasts may also contribute to disease. The purpose of this review is to discuss these findings in the context of the pathophysiology of systemic sclerosis. Recent findings: This review highlights concepts and recent findings relating to apoptosis of vascular endothelium and skin fibroblasts. Important paradigms of fibroblast cell death in wound healing and keloid formation are discussed. Recent observations describing resistance of systemic sclerosis fibroblasts to Fas-mediated apoptosis and activation of the antiapoptotic protein kinase, Akt, are mentioned as possible contributors to fibroblast selection in this disease. Summary: Improved understanding of how death and survival signals affect vascular endothelial cells and skin and visceral fibroblasts will lead to new approaches to therapy.