Osseous manifestation of infectious disease is of paramount importance to paleopathologists seeking to interpret ancient health, but the relationships among infectious agent exposure, development of disease, and skeletal involvement are complex. The outcome of an exposure strongly depends on multiple factors, including ecology, diet, nutrition, immune function, and the genetics of pathogen and host. Mycobacterial diseases are often studied in ancient remains but also are especially influenced by these factors; individual and population differences in severity and course are apparent following onset of active disease. The osteological record for these diseases represents the complex interplay of host and pathogen characteristics influencing within- and among-individual skeletal lesion prevalence and distribution. However, many of these characteristics may be assessed independently through the archaeological record. Here, we explore the contributions of dietary protein and iron to immune function, particularly the course and outcome of infection with Mycobacterium tuberculosis. We emphasize how nutrition may influence the dissemination of bacilli to the skeleton and subsequent formation of diagnostic lesions. We then generate models and hypotheses informed by this interplay and apply them to four prehistoric New World areas. Finally, discrepancies between our expectations and the observed record are explored as a basis for new hypotheses.