Although the host response to tuberculosis has been studied for many years, we still have only a rudimentary working model of the disease process; namely that antigen-specific T cells activate infected macrophages to control bacterial growth. Further progress in the control of tuberculosis will depend on a much more detailed understanding of the nature of the host response to infection. Therefore, the purpose of this Keystone Symposia meeting is to reassess our current understanding of disease mechanisms, discuss the most recent advances in the field, and identify critical questions and future research directions. A key focus of the meeting will be the innate, acquired, and immunopathologic responses that occur in the host following exposure to Mycobacterium tuberculosis. Speakers will be strongly encouraged to move past dogma and promote critical re-analysis of our working model of what constitutes protective immunity to tuberculosis. The conference will be held concurrently with a meeting on Tuberculosis: Understanding the Enemy – covering bacterial genetics, bacterial physiology, systems biology, and drug development. This will provide opportunities for participants from different disciplines to interact with one another forge new collaborations in novel areas of biology. Importantly, the interactive nature of the meetings will promote the new ideas and novel approaches necessary to combat this devastating disease.