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The worldwide public health threat of tuberculosis and the search for novel strategies for preventing and treating disease have focused attention on the interaction between host and pathogen. Despite widespread presence of Mycobacterium tuberculosis, only a relatively small percentage of people exposed to the organism progress to clinical disease. Increasing evidence indicates that host genetic factors influence the outcome of exposure to M. tuberculosis. This evidence is presented here, along with strategies used to identify host genes responsible for resistance/susceptibility in MTB infection. Studies on host genes involved in response to infection by MTB and the relationships between infection and polymorphisms in immune response genes are reviewed. Research on how host genes can influence vaccine responses and the efficacy of drugs or other interventions as well as studies into the relationship of host genes to tuberculosis outcomes may lead to new strategies for prevention and control.