Cells, tissues and organisms have the ability to rapidly switch substrate oxidation from carbohydrate to fat in response to changes in nutrient intake, and to changes in energy demands, environmental cues and internal signals. In healthy, metabolically normal individuals, substrate switching occurs rapidly and completely; in other words, substrate switching is ‘flexible’. A growing body of evidence demonstrates that a blunted substrate switching from low‐ to high‐fat oxidation exists in obese individuals, as well as in pre‐obese and post‐obese, and that this ‘metabolic inflexibility’ may be a genetically determined trait. A decreased fat oxidation can lead to a positive energy balance under conditions of high‐fat feeding, due to depletion of glycogen stores that stimulates appetite and energy intake through glucostatic and glucogenostatic mechanisms, e.g. hepatic sensing of glycogen stores. Several genetic polymorphisms and single‐nucleotide polymorphisms have been identified that are associated with low‐fat oxidation rates and metabolic inflexibility, and genetic identification of susceptible individuals may lead to personalized prevention of weight gain using fat oxidation stimulants (‘fat burners’) in the future.