SMAD4 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFss) signal pathway that controls cellular proliferation, differentiation and tissue homeostasis. The TGFss pathway suppresses tumorigenesis in premalignant states and promotes invasiveness and metastasis during cancer progression. Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS). Somatic alterations in SMAD4 are in multiple tumor types, including colon and lung adenocarcinoma. SMAD4 inactivation by allelic deletion or mutation mainly occurs in late stage pancreatic ductal adenocarcinoma and is associated with poorer prognosis. SMAD4 loss increased resistance to the chemotherapeutic agent 5'-fluorouracil. The identified deletion is not characterized but is present at a site of frequent mutations and is potentially oncogenic. The role of SMAD4 variants in small intestinal adenocarcinomas need further characterization. Clinical correlation is recommended.