Flavonoids, in particular the isoflavones, are naturally occurring compounds found in soy and textured vegetables that have antiproliferative effects on a variety of cancer types. Phenoxodiol is a derivative of the isoflavone genisten that is 5-20 times more potent than genisten. Triphendiol is a derivative of phenoxodiol that has superior anticancer activity against pancreatic and bile duct cancers. This review will focus on the mechanisms of action and activity of two isoflavone derivatives, phenoxodiol and triphendiol, in various tumor types, especially pancreaticobiliary cancers. Triphendiol induces apoptosis in pancreatic cell lines by both caspase-mediated and caspase-independent mechanisms. The addition of triphendiol to gemcitabine is synergistic in in vitro and in vivo models of pancreatic cancer and represents a novel combination of drugs for pancreatic cancer patients.