Tuberculosis is one of the most successful human diseases in our history due in large part to the multitude of virulence factors exhibited by the causative agent, Mycobacterium tuberculosis. Understanding the pathogenic nuances of this organism in the context of its human host is an ongoing topic of study facilitated by isolating cells from model organisms such as mice and non-human primates. However, M. tuberculosis is an obligate intracellular human pathogen, and disease progression and outcome in these model systems can differ from that of human disease. Current in vitro models of infection include primary macrophages and macrophage-like immortalized cell lines as well as the induced pluripotent stem cell-derived cell types. This article will discuss these in vitro model systems in general, what we have learned so far about utilizing them to answer questions about pathogenesis, the potential role of other cell types in innate control of M. tuberculosis infection, and the development of new coculture systems with multiple cell types. As we continue to expand current in vitro systems and institute new ones, the knowledge gained will improve our understanding of not only tuberculosis but all infectious diseases.