Technical Abstract: Extensive investigations have revealed that zoonotic pathogens in the Mycobacterium tuberculosis complex (MTBC) evolved from a common ancestor. Although all the members can cause disease in one or more species of mammals, Mycobacterium tuberculosis (Mtb) and M. bovis (Mbv) are the major pathogens affecting humans and livestock. The pathogens are genetically distinct, but the mechanisms by which they dysregulate the immune response and cause disease are similar, suggesting a common strategy can be used to control both pathogens. Recent advances have shown NK and NKT cells, 'd T cells and multiple newly identified T cell subsets are involved in the immune response to mycobacteria. A complex network of cytokines regulates their response to mycobacteria during the development and loss of protective immunity. Elucidation of how mycobacteria modulate the network and cause disease will provide the knowledge needed to develop an effective vaccine.