Genetic, physiological, and biochemical studies have successfully ascribed functions to genes in diverse processes. However, the majority of our knowledge in biology is qualitative in nature and is usually based on classical screens, where large effects on a qualitative phenotype are usually sought. While very essential to our mechanistic understanding, these methods can be inadequate when it comes to understanding inter-individual differences in complex quantitative traits. The intensive characterization of the Drosophila gut response to infection has led to the identification of many of its major players and canonical pathways. However, knowledge of what genes and pathways are relevant in determining inter-individual differences in a natural population is still lacking. This study addresses this question by using a systems genetics approach where the effects of natural genomic perturbations on the outcome of enteric infection are explored, often revealing unexpected determinants of infection resistance.