The study of ancient disease can now include direct analyses of all or part of the genomes of pathogens through ancient DNA techniques. Such analyses are challenging since due to several factors including preservation, pathogen load and location in the body, environmental microbial contamination, and current understanding of microbial pathogenicity. When successful, ancient DNA analyses have provided insight into the evolutionary history of a number of human and animal pathogens. In addition, recent microbiome analyses have shed light on how cultural and environmental changes have altered microbial profiles across the human body and impacted host health. In this chapter, we summarize the history and current state of the field as well as posit future directions for research associated with the study of ancient disease.