A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations, with the five most frequent being KRAS, TP53, CDKN2A, SMAD4, and ARID1A, and multiple other abnormalities seen including, but not limited to, mutations in STK11/LKB1, FBXW7, PIK3CA, and BRAF. In the era of tumor profiling, these aberrations may provide an opportunity for new therapeutic approaches. Here, SMAD4 is linked to familial pancreatic carcinoma.