Dietary patterns have repeatedly been shown to have profound effects on health when studied at the population level. For example, Japanese and Mediterranean diets are associated with longevity and low rates of various chronic diseases. Western diets are associated with increased risk of heart disease and certain types of cancer. However, studies evaluating dietary interventions in individuals find significant variations in responses. Much of this variation is likely because of underlying genetic differences among individuals. To determine how diet affects pathophysiological responses in different genetic backgrounds, we examined cardiometabolic-related effects of five diets (current Western diet, traditional Mediterranean diet, traditional Japanese diet, a ketogenic diet and standard mouse chow) in each sex of four inbred mouse strains (A/J, C57BL/6J, FVB/NJ, and NOD/ShiltJ) selected for their known disparate susceptibilities to cancer, diabetes, and other diseases. Mice were fed diets ad libitum for six months while undergoing a variety of clinical analyses. We found that many health-related diet responses are dependent upon genetic background including: adiposity, glucose tolerance, blood chemistry profiles, liver triglyceride storage, liver mitochondrial function, and metabolic rate. The severity and directionality of many of these diet responses differ depending on the genetic background of the individual. For example, C57BL/6J mice became obese and showed signs of cardiometabolic distress on a Western diet but maintained good health on a ketogenic diet; FVB/NJ mice had minimal fat gain and were relatively healthy on a Western diet but became obese and suffered cardiometabolic distress on a ketogenic diet. Most strains had positive health profiles on the Japanese diet, while the health of A/J mice differed little across diets. Mouse strains differed as to which diets were optimal or suboptimal, suggesting that human individuals likely have a specific diet for optimal health based upon their unique genetic makeup. These results call into question the categorization of diets as good or bad and emphasize the need to evaluate dietary efficacy on an individual level. Follow-up studies are investigating the genetic factors underlying the different diet responses with the ultimate goal of allowing accurate prediction of diet response in genetically diverse human individuals.