Optimum immunity against Mycobacterium tuberculosis requires both CD4 + and CD8 + T cells. In contrast with CD4 + T cells, few antigens are known that elicit CD8 + T cells during infection. CD8 + T cells specific for culture filtrate protein-10 (CFP10) are found in purified protein derivative positive donors, suggesting that CFP10 primes CD8 + T cells in vivo. Using T cells from M. tuberculosis –infected mice, we identified CFP10 epitopes recognized by CD8 + T cells and CD4 + T cells. CFP10-specific T cells were detected as early as week 3 after infection and at their peak accounted for up to 30% of CD8 + T cells in the lung. IFNγ-producing CD8 + and CD4 + T cells recognizing CFP10 epitopes were preferentially recruited to the lungs of M. tuberculosis –infected mice. In vivo cytolytic activity of CD8 + T cells specific for CFP10 and TB10.3/10.4 proteins was detected in the spleen, pulmonary lymph nodes, and lungs of infected mice. The cytolytic activity persisted long term and could be detected 260 d after infection. This paper highlights the cytolytic function of antigen-specific CD8 + T cells elicited by M. tuberculosis infection and demonstrates that large numbers of CFP10-specific cytolytic CD8 + T cells are recruited to the lung after M. tuberculosis infection.