Obesity is the strongest risk factor for type 2 diabetes, however, excess body fat does not fully explain the etiology of diabetes as several human populations develop diabetes at a lower level of obesity than others, and about 20% of obese people display normal metabolism. A major recommendation is to reduce calorie intake, yet the contribution of individual macronutrients to individuals risk of developing metabolic diseases is poorly understood. There is no clear consensus on what comprises the optimal healthy diet, and emerging evidence shows tremendous variation on health effects of different diets between individuals and populations. The aim of this study was to understand how the genetic background defines a framework for a healthy diet. To this end, we have used the Drosophila Genetic Reference Panel (DGRP), a collection of 200 inbred fly strains derived from a single outbred natural population, to dissect the gene-diet interaction across various macronutrients. Our study shows that genetic background determines the survival of flies on different diets. Functional validation of candidate SNPs identified a large number of genes previously unknown to control the metabolism and utilization of macronutrients. Isolating genes that predispose to better health outcomes in response to different nutrients will have considerable impact on public health and provides a first step towards the development of personalized nutrition as a practice to manage metabolic diseases.