Disruption of the adaptor protein ELF, a β-spectrin, leads to disruption of transforming growth factor–β (TGF-β) signaling by Smad proteins in mice. Elf −/− mice exhibit a phenotype similar to smad2 +/− / smad3 +/− mutant mice of midgestational death due to gastrointestinal, liver, neural, and heart defects. We show that TGF-β triggers phosphorylation and association of ELF with Smad3 and Smad4, followed by nuclear translocation. ELF deficiency results in mislocalization of Smad3 and Smad4 and loss of the TGF-β–dependent transcriptional response, which could be rescued by overexpression of the COOH-terminal region of ELF. This study reveals an unexpected molecular link between a major dynamic scaffolding protein and a key signaling pathway.