Obesity and its associated co-morbidities provide powerful examples of the complexity of gene-environment interactions in which the multiplicity of phenotypic responses that result from environmental challenges are significantly influenced by underlying genetic variations. While the development of obesity is closely linked to the consumption of diets high in calories and fat, not everyone exposed to such a diet becomes obese. Furthermore, since obesity can co-occur with insulin resistance, dyslipidemia and hypertension often enough to warrant the term "metabolic syndrome", these additional phenotypic responses provide important distinctions of otherwise similarly obese individuals. This phenotypic diversity suggests that understanding obesity susceptibility alone will not be sufficient to uncover the genetic variants that are predictive of its co-morbid diseases nor of the optimal or tolerable biological states for genetically diverse individuals. Inbred strains of mice are emerging as a valuable resource to dissect genetic interactions that mediate sensitivity to diet-induced obesity from those that drive susceptibility to diseases like atherogenesis and insulin resistance. Mice, like humans, exhibit varying sensitivity and resistance to both diet-induced obesity and co-morbidities. Using genetically controlled animal models, here, Shockley et al. have exploited a set of ten inbred strains with established differences in atherogenic and obesogenic responses to a Western-style high fat diet and here have profiled diet-induced changes in hepatic gene expression. Diet-induced gene expression patterns ranged from largely independent of genetic variation to those highly modified by strain, gender, as well as tightly correlated to quantitative phenotypic responses. The results provide a powerful new resource to explore the relative co-variance of genetic variations, genomic expression pattern signatures, and a battery of pathologic and physiologic processes. Exploiting these kinds of resources should catalyze the discovery of underlying pathways, disease mechanisms and translational implications for individuals with variant genetics attempting to optimize their health in challenging environments.