We propose that a recent change in the conception of the role of type 1 interferon and the identification of adventitial stem cells suggests a unifying hypothesis for scleroderma. This hypothesis begins with vasospasm. Vasospasm is fully reversible unless, as proposed here, the resulting ischemia leads to apoptosis and activation of type 1 interferon. The interferon, we propose, initiates immune amplification, including characteristic scleroderma-specific antibodies. We propose that the interferon also acts on adventitial stem cells, producing myofibroblasts, rarefaction, and intimal hyperplasia--three morphologic changes that characterize this disease. Regulator of G-protein signaling 5 (RGS5), a regulator of vasoactive G-protein-coupled receptors, is a cell type-specific marker of pericytes and scleroderma myofibroblasts. RGS5 may provide a key link between initial hyperplasia and fibrosis in this disease.