Nontuberculous mycobacteria (NTM) are ubiquitous components of the soil and surface water microbiome. Disparities by sex, age, and geography demonstrate that both host and environmental factors are key determinants of NTM disease in populations, which predominates in the form of chronic pulmonary disease. As the incidence of NTM pulmonary disease rises across the United States, it becomes increasingly evident that addressing this emerging human health issue requires a bold, multi-disciplinary research framework that incorporates host risk factors for NTM pulmonary disease alongside the determinants of NTM residence in the environment. Such a framework should include the assessment of environmental characteristics promoting NTM growth in soil and surface water, detailed evaluations of water distribution systems, direct sampling of water sources for NTM contamination and species diversity, and studies of host and bacterial factors involved in NTM pathogenesis. This comprehensive approach can identify intervention points to interrupt the transmission of pathogenic NTM species from the environment to the susceptible host and to reduce NTM pulmonary disease incidence.