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Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, provides variable efficacy against adult pulmonary TB, but why this protection varies is unclear. Humans are regularly exposed to non-tuberculous mycobacteria (NTM) that live in soil and water reservoirs and vary in different geographic regions around the world. Immunologic cross-reactivity may explain disparate outcomes of BCG vaccination and susceptibility to TB disease. Evidence supporting this hypothesis is increasing but challenging to obtain due to a lack of reliable research tools. In this review, we describe the progress and bottlenecks in research on NTM epidemiology, immunology and heterologous immunity to Mtb. 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