The poor treatment outcomes for extensively drug-resistant and multidrug-resistant tuberculosis and the slow progress in development and evaluation of new tuberculosis drugs gave rise to development of several potential immune-based therapies for adjunct use with drug treatment. However, none of these therapies have been shown to be of benefit in controlled clinical trials in humans. There is an urgent need to rethink the immunology of Mycobacterium tuberculosis infection and to ascertain protective immune mechanisms that could be exploited to develop more effective adjunct immune therapies. T cells obtained from the peripheral blood circulation may not reflect the biologically relevant recognition of anti-M. tuberculosis T-cell responses in situ. Thus, T cells that mediate protective anti-M. tuberculosis immune responses recognize an as-yet undiscovered set of M. tuberculosis antigens that require definition. The biologically and clinically relevant M. tuberculosis targets that elicit protective immune responses may have yet to be discovered. The entire M. tuberculosis proteome is now accessible for screening by antibody recognition and can therefore be used to identify specific T-cell M. tuberculosis target antigens. Inhibitory cytokines and lymphocytosis present in chronic tuberculosis inflammation may be deleterious in mounting an effective M. tuberculosis T-cell response. Consequently, aberrant and noneffective immune responses could be refocused with anticytokine or cellular therapy. Epigenetic changes due to chronic inflammation may be responsible, in part, for impaired immune responses in tuberculosis and these changes could be reversed. We present feasible experimental designs to test these hypotheses; the results of which may guide and refocus development of novel immune-based therapies for adjunct treatment of drug-resistant tuberculosis. Insights from cancer immunology will cross-fertilize tuberculosis immunology and help to devise more effective adjunct treatment and vaccination strategies.