Cumulative evidence shows that fibrogenic stroma and stiff extracellular matrix (ECM) not only result from tumor growth but also play pivotal roles in cellular transformation and tumor initiation. This emerging concept may largely account for the increased cancer risk associated with environmental fibrogenic agents, such as asbestos and silica, and with chronic conditions that are fibrogenic, such as obesity and diabetes. It may also contribute to poor outcomes in patients treated with certain chemotherapeutics that can promote fibrosis, such as bleomycin and methotrexate. Although the mechanistic details of this phenomenon are still being unraveled, we provide an overview of the experimental evidence linking fibrogenic stroma and tumor initiation. In this Review, we will summarize the causes and consequences of fibrous stroma and how this stromal cue is transmitted to the nuclei of parenchymal cells through a physical continuum from the ECM to chromatin, as well as ECM-dependent biochemical signaling that contributes to cellular transformation.