The pathogenesis of fibrosis in scleroderma involves a complex set of interactions between the fibroblast and its surroundings. Multiple fibrotic pathways are activated for reasons that are not completely clear, but involve immune activation, microvascular damage, and fibroblast transformation into the myofibroblast. Differential proliferation and apoptosis preserve the myofibroblast phenotype rather that leading to a selective depletion of activated fibroblasts after an acute injury has healed. Disproportionate fibroblast activity could result from a combination of possible cellular and matrix defects that include fibrillin protein abnormalities, autoantibody formation, type II immune response, excessive endothelial reaction to injury, and excessive fibroblast response to TGF-beta. Development of therapies that are targeted to correcting these abnormalities will eventually lead to effective treatment for the fibrotic complications of scleroderma.