Even closely related individuals vary in their response to infection. In this dissertation, I combined the fruit fly model system with multiple pathogens, including 16 strains of the fungus Metarhizium, to dissect how pathogens with different virulence strategies interact with variable host resistance and tolerance mechanisms. I began by infecting 188 sequenced Drosophila melanogaster lines [the Genetic Reference Panel (DGRP)] with broad host range Metarhizium anisopliae (Ma549) or the bacterium Pseudomonas aeruginosa (Pa14, originally from a human host). Resistance to the two pathogens was correlated (suggestive of general multipurpose defense mechanisms) and associated with oxidative stress sensitivity, starvation resistance, and in particular sleep indices (flies that take a lot of naps are particularly resistant to disease). I followed up by showing that this nonspecific defense extends to the specialist co-evolved Drosophila pathogen, Entomophthora muscae. A genome wide association study implicated several metabolic pathways and physiological processes in individual variation to disease, but not the canonical antifungal Toll immune pathway.Indeed, Metarhizium strains that killed faster induced a stronger and earlier Toll immune response, indicating virulence does not depend on suppressing immunity. Disrupting the Toll pathway component Dif only increased susceptibility to the early diverged broad host range Metarhizium frigidum, whereas flies disrupted in Persephone (a sensor of pathogen proteases) succumbed quickly to all Metarhizium strains. Microarray analysis of mutants revealed a suppressed transcriptomic response to infection when either Persephone or Dif were disrupted, with overlap with GWAS-implicated pathways.