Studies of the ancient history of infectious diseases have been facilitated greatly by development of a succession of novel analytical methods. In particular, laboratory analytical methods that are based on high-throughput ancient deoxyribonucleic acid sequencing have received considerable attention in this respect. Even so, significant environmental caveats remain. There are many means by which microbes move through soil, often fairly readily. Thus, the depositional component of the postmortem environment, especially with respect to unshielded animal or human remains, is a fertile arena for many microbes that can contaminate archaeological specimens well after deposition and decay of soft tissues. The huge number of pathogenic and nonpathologic genera and species clearly dictate renewed interest and research into the long-term biological activities of soil-covered remains. In a tuberculosis context, we focus on various depositional concerns and limitations, such as contamination prior to archaeological discovery (perhaps many years prior), various means of microorganism movement in soil, the influence of these factors on differential diagnosis, and real hazards for misinterpretation of investigational results.