The mouse provides a tool with which to probe the complex interaction between the mammalian immune system and the slow-growing, inflammatory, and persistent bacterium, Mycobacterium tuberculosis (Mtb). Simple mouse models using genetic deletion or antibody inhibition have identified causal connections between specific components of the immune response and survival upon challenge with Mtb, and these studies have corresponded with observations made in humans. To improve on current intervention strategies, it is essential that the complex interactions between the components of the immune response that mediate and regulate the protective response to Mtb infection be dissected; furthermore, the pathways by which specific molecules and cells act must be delineated. The mouse model provides a tool with which to achieve this goal; however, experimental design and data interpretation must be made in the context of data sets generated from the entire tuberculosis field.