Biotechnological approaches have been applied to introduce resveratrol-synthase (RS ) (aka. Stilbene synthase ) into novel crops such as apple, kiwi, tomato and wheat. As with natural sources of resveratrol, genetically-modified plants, which constitutively express RS, accumulate resveratrol primarily in the form of piceid (RG). The chemopreventive activity of a RG-accumulating transgenic alfalfa (variety Regen SY) against colon cancer was assessed in an azoxymethane (AOM)-induced aberrant crypt foci (ACF) rodent model of carcinogenesis. Our initial studies revealed that the transgenic alfalfa (TA) at 20% in the diet by weight had no affect on the number, size or multiplicity of ACF in CF-1 mice after a five-week feeding trial. However, the number of AOM-induced ACF was reduced in mice fed these diets supplemented with a β-glucosidase enzyme relative to mice fed TA alone. To test that RG is not bioavailable to the colon, the colonic concentrations of resveratrol-aglycone (Rag) and RG were measured following five-week administration of the diets. Rag, but not RG, was detected by liquid chromatography/mass spectrometry in the colons of mice fed transgenic alfalfa, but these concentrations tended to be lower in mice fed TA without α-galactosidase relative to mice fed these diets supplemented with enzyme. The use of a lactase inhibitor in transport studies conducted in everted, jejunal sacs from CF-1 mice suggested that RG was a substrate for lactase-phlorizin hydrolase and can be absorbed intact in the intestines, also. However, comparative studies with Rag suggest that the intestinal absorption of the Rag was much more efficient than that of RG. Rag could be detected in the plasma and the epithelia of the colon and small intestine of CF-1 mice intragastrically fed 25 mg (111 μM) Rag/kg body weight 1-7 hours post-gavage, but neither Rag nor RG could be detected in mice fed an equal dose of piceid at these time points. Collectively, these data suggest that the intestinal bioavailability of RG was much less than that of Rag. The findings of these studies raise doubt on the ability to achieve the purported health benefits of resveratrol through natural sources alone where resveratrol is present as RG.