Highlights • NTM infections are due to acquired or genetic host susceptibility factors. • Multiple minor gene mutations collaborate to increase vulnerability to NTM-LD. • NTM cell wall products play roles in disease pathogenesis and host immune response. Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and human exposure is likely to be pervasive; yet, the occurrence of NTM-related diseases is relatively infrequent. This discrepancy suggests that host risk factors play an integral role in vulnerability to NTM infections. Isolated NTM lung disease (NTM-LD) is often due to underlying anatomical pulmonary or immune disorders, either of which may be acquired or genetic. However, many cases of NTM-LD have no known underlying risk factors and may be multigenic and/or multicausative. In contrast, extrapulmonary visceral or disseminated NTM diseases almost always have an underlying severe immunodeficiency, which may also be acquired or genetic. NTM cell wall components play a key role in pathogenesis and as inducers of the host immune response. [ABSTRACT FROM AUTHOR]