Flavonoids are a diverse group of secondary metabolites found ubiquitously in the plant kingdom. Many flavonoids are used as nutraceutical supplements but a growing number of unnatural flavonoids are being investigated as therapeutic agents. Our group has been focusing on utilizing metabolic engineering and organic chemistry approaches in order to synthesize natural plant flavonoids (isoflavones, flavanones, flavones, dihydroflavonols, stilbenes, flavonols, catechins and anthocyanins) and non-natural derivatives with the ultimate purpose of using them for diabetes and obesity treatment. Our progress has covered the reconstruction of the plant biosynthetic pathway within both Escherichia coli and Saccharomyces cerevisiae. We have been able to increase flavonoid production yields by either introducing additional enzymes or inhibit competing pathways to increase intercellular pools of necessary auxiliary compounds such as malonyl-CoA and UDP:glucose for biosynthesis of specific flavonoids. In addition, we have explored the synthesis of novel flavonoid analogs using mutasynthesis approaches as well as more established organic syntheses methodologies. Studies conducted in our lab as well as in collaboration efforts have shown that these compounds have significant biological activity towards digestive enzyme inhibition and up regulation of insulin secretion from pancreatic beta-cells.