PDGF signaling regulates the development of mesenchymal cell types in the embryo and in the adult, but the role of receptor activation in tissue homeostasis has not been investigated. We have generated conditional knockin mice with mutations in PDGFRα that drive increased kinase activity under the control of the endogenous PDGFRα promoter. In embryos, increased PDGFRα signaling leads to hyperplasia of stromal fibroblasts, which disturbs normal smooth muscle tissue in radially patterned organs. In adult mice, elevated PDGFRα signaling also increases connective tissue growth, leading to a progressive fibrosis phenotype in multiple organs. Increased PDGFRα signaling in an Ink4a/Arf-deficient genetic background leads to accelerated fibrosis, suggesting a new role for tumor suppressors in attenuating fibrotic diseases. These results highlight the role of PDGFRα in normal connective tissue development and homeostasis and demonstrate a pivotal role for PDGFRα signaling in systemic fibrosis diseases.