Fungal diseases have recently caused severe multi-species die-off events in wildlife. In particular, chytridiomycosis, a skin disease caused by the chytrid pathogen Batrachochytrium dendrobatidis (Bd), has provoked extinctions and severe declines in many amphibian populations across the globe. Here, I investigate the combination of environmental, ecological, and genetic factors that determine a species' ability to persist despite infection. In Chapter 1, I review recent literature-including experimental Bd challenges and longitudinal studies-to illustrate how integrating genomic approaches into current research, both for hosts and pathogens, will improve our understanding of factors promoting disease outcome. In Chapter 2, I apply a traitbased approach to investigate how species-specific attributes control the degree of exposure, probability of infection, and pathogen intensity, during and after Bd emergence in a naïve amphibian community at El Copé, Panamá. I find a signature of phylogenetic history in disease responses associated with increased pathogen exposure via shared life history traits such as reproductive mode and habitat use. I identify key hosts at the time of Bd emergence, characterized by a high probability of infection, pathogen load, and abundance. In Chapter 3, I characterize temporal turnover of skin microbial communities and their relation to Bd prevalence and infection intensity in three natural populations of the common coqui (Eleutherodactylus coqui) in Puerto Rico that persist with enzootic Bd infections. I find that natural fluctuations in temperature and precipitation between months can create opportunities for microbial replacement, potentially attenuating pathogen transmission, and thus contributing to host persistence in E. coqui populations. In Chapter 4, I experimentally infect E. coqui frogs under conditions known to confer the survival advantage to the host, or alternatively to the pathogen, by performing inoculations in mesocosms over two seasons. I demonstrate that natural fluctuations in environmental conditions shift the survival advantage among the pathogen, the host, and its microbial community. In summary, my results advance our understanding of multi-host single-pathogen systems by quantifying the relative roles of host heterogeneity and environmental controls at different disease stages after pathogen emergence.