The human immune response does an excellent job of clearing most of the pathogens that we encounter throughout our lives. However, some pathogens persist for the lifetime of the host. Despite many years of research, scientists have yet to determine the basis of persistence of most pathogens, and have therefore struggled to develop reliable prevention and treatment strategies. Systems biology provides a new and integrative tool that will help to achieve these goals. In this article, we use Mycobacterium tuberculosis as an example of how systems-biology approaches have begun to make strides in uncovering important facets of the host-pathogen interaction.