The fungus Metarhizium anisopliae is a natural pathogen of fruit flies. We performed a screen of 2,613 mutant Drosophila lines to identify host genes affecting susceptibility to M. anisopliae 549. In addition, we used Drosophila gene disruption mutants and reporter lines such as drosomycin-GFP to examine variation in Drosophila’s responses to GFP or RFP tagged Metarhizium strains with different infection strategies (e.g., quick kill via toxins vs. slow kill via invasive growth), and different lifestyles (generalist broad host range strains with different degrees of virulence to Drosophila and specialists with narrow host ranges that show poor infectivity to Drosophila). To investigate the impact of pathogen and host variation on fungal fitness and host survival we looked at correlations between key life history traits at different steps of the infection process; lethal pathogen dose (LD50), within-host growth (fungal load), host life span (LT50 values), latent period (the lag time between inoculation and sporulation), and sporulation capacity (the total number of spores per Drosophila cadaver). By analyzing fungal behavior post infection we identified environmental as well as genetic determinants influencing Drosophila pathogen interactions. Drosophila mutants disrupted in immune related genes showed increased susceptibility to specialist Metarhizium’s adapted to other insects, but mutations had less effect on generalists. Testing isolated components of the Drosophila immune response demonstrated that the antifungal peptide Drosomycin did not inhibit Metarhzium strains alone nor in combination with cecropin A.