The pathogenesis of systemic sclerosis (SSc; scleroderma) remains poorly understood. Fortunately, it is now possible to focus research strategies on a variety of cell types, receptors, and informational molecules (I). In this review, we will summarize and criticize the available data implicating 6 cell types (fibroblasts, endothelial cells, platelets, monocytes, lymphocytes, and mast cells) and 3 receptor-ligand systems (transforming growth factor (3 [TGF-{3], platelet-derived growth factor [PDGF], and tumor necrosis factor [TNF]/lymphotoxin) that are presently considered relevant to the vascular intimal proliferation, the microvascular (capillary) obliteration, and the interstitial fibrosis that characterize SSc (2, 3).