CD8 T cells have been shown to be protective against Mycobacterium tuberculosis infections in the mouse. These cells have been shown to be cytolytic toward M. tuberculosis-infected cells and have also been shown to release the protective cytokine gamma interferon in response to mycobacterial antigen. It has therefore been unclear how these cells mediate their protective response. To dissect this problem, we compared the courses of M. tuberculosis infections in control, perforin gene-knockout, and granzyme gene-knockout mice exposed by the realistic pulmonary route. The inability to express either of these molecules limits the expression of the major lytic pathway but does not appear to influence the course of the infection or result in any discernible histologic differences. These data seem to rule against a lytic role for CD8 T cells in the lungs and hence tend to suggest instead that another type of mechanism, such as cytokine secretion by these cells, is their primary mode of action.