Many of the signaling responses induced by transforming growth factor-β (TGF-β) are mediated by Smad proteins, but there is evidence that it can also signal independently of Smads. Here, we provide evidence that multiple signal pathways induced by TGF-β1—including Src family tyrosine kinases (SFKs), generation of reactive oxygen species (ROS), de novo protein synthesis and E-cadherin-dependent cell–cell interactions—transactivate the epidermal growth factor receptor (EGFR), which in turn regulates expression of c-Fos and c-Jun. Immunoprecipitation and immunofluorescence staining showed that EGFR was phosphorylated on tyrosine in response to TGF-β1. EGFR transactivation required the activation of SFKs and the production of ROS via NADPH oxidase, but was not dependent on metalloproteases or the release of EGF-like ligands. In addition, the production of ROS was dependent on signaling by specific SFKs as well as de novo protein synthesis. Stable transfection of E-cadherin into MDA-MB-231 cells as well as E-cadherin-blocking assays revealed that E-cadherin-mediated cell–cell interactions were also essential for EGFR transactivation. Finally, EGFR transactivation was involved in the expression of c-Fos and c-Jun via the extracellular signal-regulated kinase signaling cascade. Taken together our data suggest that ligand release-independent transactivation of EGFR may diversify early TGF-β signaling and represent a novel pathway leading to TGF-β-mediated gene expression.