Cardiometabolic risk is a common condition characterized by obesity, atherogenic dyslipidemia, inflammation and hypertension, which is associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Among the environmental factors, diet is one of the most important environmental factors modulating the expression of genes involved in metabolic pathways and the variety of phenotypes associated with obesity, the metabolic syndrome and T2DM. Nutritional genomics provides a genetic understanding as to how dietary components affect the balance between health and disease by altering the expression and/or structure of an individual's genetic makeup. Dietary components can play a role in participating in the modulation of gene expression. The studies of transcriptomics in nutrition intervention studies can determine the molecular impact on nutritional management strategies. For example, fisetin is one of the most predominant flavonols occurring in strawberries and there is limited information on the potential metabolic effects of fisetin. We aimed to test whether fisetin could modulate cholesterol homeostasis and hepatic lipogenesis in rats fed high fat diets, and further investigated the underlying mechanisms by which fisetin exerts its metabolic effects in high fat fed rats. The results showed that fisetin supplementation decreased cardiometabolic risks by ameliorating hypercholesterolemia and hepatic steatosis. In addition, these effects were achieved by modulating genes involved in cholesterol metabolism, hepatic lipogenesis and gluconeogenesis in the liver. The results raise the possibility that fisetin may be used as a single supplement, or in combination with other therapeutic agents, in the prevention and/or treatment of cardiometabolic risks. This study was carried out with the support of "Cooperative Research Program for Agricultural Science & Technology Development (Project No.PJ010975)", Rural Development Administration, Republic of Korea.