An organism encounters an extensive range of dietary choices in its niche. The macronutrient and micronutrient quotients of these diets instruct downstream molecular events, eventually orchestrating complex physiological responses that determine their life-history traits. In response to diverse nutritional inputs, organisms deploy multiple adaptive mechanisms to maintain optimal life span and health. However, we know little about these processes. Although we have come to appreciate the complex relationship between diet and genes in modulating life span in response to diverse nutritional inputs, it can be difficult to identify these interactions in the laboratory, as an organism maintains a normal life span on a wide range of diet. But in rare cases, a mutant laboratory animal, with the mutation attributable to a single gene, may display altered physiological traits on only one diet but not on others. These 'diet-gene pairs' contribute immensely to our understanding of how diet quality influences physiological traits like longevity and health.