Mycobacteria are intracellular pathogens that have macrophages as their main host cells. However, macrophages are also the primary line of defense against invading microorganisms. To survive in the intracellular compartment, virulent mycobacteria have developed several strategies to modulate the activation and the effector functions of macrophages. Despite this, antigen-specific T cells develop during infection. While T cell responses are critical for protection they can also contribute to the success of mycobacteria as human pathogens, as immunopathology associated with these responses facilitates transmission. Here, we provide a brief overview of different immune-evasion strategies of mycobacteria and their impact on the protective immune response. This understanding will further our knowledge in host-pathogen interactions and may provide critical insights for the development of novel host-specific therapies.