Tissue microbiology allows for the study of bacterial infection in the most clinically relevant microenvironment, the living host. Advancements in techniques and technology have facilitated the development of novel ways of studying infection. Many of these advancements have come from outside the field of microbiology. In this article, we outline the progression from bacteriology through cellular microbiology to tissue microbiology, highlighting seminal studies along the way. We outline the enormous potential but also some of the challenges of the tissue microbiology approach. We focus on the role of emerging technologies in the continual development of infectious disease research and highlight future possibilities in our ongoing quest to understand host-pathogen interaction.