To better understand the molecular mechanisms underlying energetic efficiency and obesity development in mammals, genes differentially expressed in a longterm, porcine model of obesity development were evaluated. The model consisted of eighty pigs from a single genetic strain and rearing environment receiving a caloric intake equivalent to 1.8 times their daily body maintenance from a nutrient mix representative of an American diet for 144 days. Pigs (8 /group) with the highest and lowest energetic efficiency (EE) were identified and differential gene expression of over 10,000 gene transcripts in adipose, muscle and liver tissues was evaluated via a porcine specific microarray. Dietary ME intakes and body weight gains were similar between the two EE groups but high EE animals accrued 52% more energy and 76 % more body fat tissue. Microarray analysis revealed marked differences (p<0.05; >1.5 fold difference) in expression of over 100, 200, and 150 genes in adipose, muscle and liver tissues, respectively. Expression of genes involved in fatty acid metabolism were expressed at significantly higher levels in the low EE group, whereas expression of some genes involved in ATP synthesis, lipogenesis and cholesterol synthesis, were expressed at significantly higher levels in the high EE group. Interestingly, genes implicated in defense and stress responses, such as heat shock proteins and some cytokines, were also expressed at higher levels in the high EE group. Additionally, a number of previously unappreciated regulatory molecules were identified that may be influencing energetic efficiency in mammals independent of energy intake. These results aid in the identification of novel genes and molecules involved in modulating energetic efficiency and the development of the obesity phenotype in mammals independent of energy intake.