Host defense against pathogenic infection is composed of resistance and tolerance. Resistance is the ability of the host to limit a pathogen burden, while tolerance is the ability of the host to limit the negative impact of a given pathogen burden. This distinction recognizes that the fittest host may not have the most aggressive immune system, and that host-pathogen coevolution consists of more than an escalating arms race between pathogen virulence factors and host antimicrobial activity. Studies of animal defenses have focused almost completely on resistance, while ignoring potential tolerance mechanisms. In this dissertation, I use a quantitative framework to characterize patterns of natural variation in resistance and tolerance in Drosophila melanogaster. I identify the relationship between these traits, associated evolutionary costs of each strategy, and how they are altered by environmental context. Using a genome-wide association study approach, I identify the genetic basis of natural variation in tolerance and resistance, and show that while variation in resistance is explained by polymorphisms in genes involved in the canonical humoral immune response, tolerance is determined by polymorphisms in genes that regulate transcriptional activity of the immune system and metabolic processes. Using patterns of allelic variation, I show balancing selection and mutation selection balance may be acting on polymorphisms that explain phenotypic variation in defense.