Although receptor-phosphorylated Smads or TGF-β receptors can be mutated or deleted in some cancers,4 Smad4 appears to be the main barrier to tumor progression and is frequently mutated, with devastating effects, in prostate and pancreatic carcinomas.5 Mutations in Smad4/DPC4 have been identified in approximately 50% of pancreatic adenocarcinomas,6,7 suggesting a pivotal role during pancreatic cancer progression. The gene discussed is SMAD4; the disease is familial pancreatic carcinoma.