The disease chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), emerged in the 1970s and has caused the decline and extinction of hundreds of amphibian species worldwide. Several pathogen and environmental factors have been identified that play critical roles in determining Bd disease dynamics. In comparison, host factors have been infrequently characterized and remain poorly understood. Here, I explore genetic responses to Bd in the lowland leopard frog (Lithobates yavapaiensis) to evaluate the hypothesis that host genetic factors contribute to Bd susceptibility across natural populations. I characterize disease prevalence, environmental variables, and measures of genetic variability in eleven natural populations to reveal spatial and temporal Bd dynamics. I also perform experimental Bd infections in lab-reared frogs collected from five natural populations. For both experimentally reared frogs and natural populations, I characterize allelic variation at an expressed Major Histocompatibility Complex (MHC) class IIB locus that encodes peptides that initiate acquired immunity. I find that infections are minimal in summer but abundant in winter, some populations are Bd infected without developing chytridiomycosis, and other populations are Bd infected and experience fatal bouts of chytridiomycosis. I identify an outlier locus that shows associations to Bd susceptibility, and find the best models predicting Bd dynamics include both genetic diversity and environmental variables. I show that MHC alleles associate with surviving Bd infection in both lab-infected frogs and naturally sampled iv individuals. Individuals bearing MHC allele Q show significantly reduced risks of death, and I detect positive selection along the evolutionary lineage leading to allele Q. Further, in one Bd resistant population, I detect a significant signal of directional selection for allele Q. For lab-infected frogs only, MHC heterozygotes also have a significantly reduced risk of death. In summary, I find that population genetic and immunogenetic variation contributes to Bd susceptibility after controlling for environmental variation, demonstrating that host genetics significantly affect chytridiomycosis outcomes and may be a powerful tool for conserving global amphibian biodiversity. v