Dietary flavonoids and other polyphenols have many biological properties that could make them useful as chemopreventive agents. However, very poor oral bioavailability makes them largely ineffective in vivo. The low bioavailability is mainly due to highly efficient glucuronic acid and sulfate conjugation of these mono- or polyhydroxylated agents in the intestinal/hepatic barrier. This review describes how the methyl capping of all free hydroxyl groups of flavones results in dramatically increased metabolic stability, as the metabolism is shifted to less efficient CYP-mediated oxidation. This was demonstrated best by using the human liver S9 fraction with an appropriate selection of cofactors. In addition, the intestinal transport of flavones was much improved through methylation, as shown in Caco-2 cell Transwell experiments. In vivo in the rat, oral administration of one methylated flavone resulted in high bioavailability and tissue distribution with no detectable levels of its unmethylated analogue. In addition to increased metabolic stability, methylation resulted in markedly increased inhibition of cancer cell proliferation. Thus, methylation appears to be a simple and effective way of increasing both metabolic resistance and transport of the flavonoids and, most important, some of their major biological activities.