Tuberculosis (TB) remains a major global health problem, because (i) diagnosis is usually made too late to avoid spread of infection to contacts; (ii) vaccination with bacillus Calmette‐Guerin (BCG) does not prevent the most prevalent pulmonary disease; and (iii) defaulting from lengthy chemotherapy leads to an increase in drug resistant strains. The continued impact of human immunodeficiency virus (HIV) co-infections remains a major aggravating factor in TB resurgence. Intensive research on the specificity and function of immunological responses is of major importance since protective host defense is critically dependent on T cells, which selectively recognize only certain antigens and epitopes of the tubercle bacillus. Such knowledge is therefore necessary for designing a novel effective vaccine and better diagnostic tools. The specificity of the host immune response may also help to explain how the intracellular tubercle bacilli evade host resistance, probably by decoy pro-inflammatory actions of some of their antigens and/or immunomodulatory constituents, which lead to chronic infection and lung pathology. The 12 articles in this Research Topic in the section Microbial Immunology of the journal Frontiers in Immunology review current knowledge, as well as gaps in our understanding of the mechanisms and functions of T and B cell recognition of antigens and constituent epitopes of Mycobacterium tuberculosis (Mtb). The abundant occurrence of major histocompatibility complex (MHC) class II-permissive epitopes in tubercle bacilli has important implications for the development of both subunit vaccines and diagnostic tests (1, 2). Moreover, an evolutionary interpretation has been that selection of Mtb strains carrying protective MHC-permissive epitopes could have extended the survival of infectious individuals and hence was advantageous for the protracted aerosol transmission of the pathogen (1).