Increasing interest in the vascular features of scleroderma has led to the hypothesis that the blood vessel is the major target tissue and that the endothelial cell is the principal cell target. Useful observations stemming from the vascular hypothesis include the use of microvascular abnormalities in the early detection of the patient destined to develop classical scleroderma, the discovery of a serum protease selectively cytotoxic to endothelial cells, and the study of a serum mitogenic activity for fibroblasts in scleroderma patients. Immune events related to the vascular lesions are under active study but have not as yet provided a unique immunological lesion in scleroderma patients. The possibility that immunity to basement membrane (type IV) collagen may be selective for scleroderma patients deserves further study. Persistent immunity to endothelial basement membrane structures would provide a basis for continued endothelial injury. Techniques to quantify endothelial injury are useful to assess activity of the vascular lesions and to monitor therapies designed to block further vascular injury. The definition of pre-fibrotic vascular lesions may have future therapeutic and preventive implications for scleroderma.