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The lungs are the most common disease site of nontuberculous mycobacteria (NTM). However, the isolation of NTM in a respiratory specimen does not indicate lung disease (LD). Differentiation between NTM colonization and NTM-LD remains challenging. In this brief review, we summarize the clinical impact of NTM-LD on morbidity and mortality in high-risk populations. The diagnosis criteria for NTM-LD—including clinical features, radiological presentations, and microbiological evidence—are also reviewed, according to the latest American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) guideline and the British Thoracic Society (BTS) guideline. However, the diagnosis of NTM-LD does not necessitate the initiation of anti-NTM treatment. Both environmental, host, and bacterial factors should be considered to identify patients that require NTM-LD treatment.