Non-tuberculous mycobacteria (NTM) are environmental bacteria that have become increasingly prevalent globally, with rising incidence rates and projected increases without new interventions. Current treatments for NTM infections, particularly for Mycobacterium avium complex (MAC), require a three-drug regimen for about 18 months, with variable success rates and high relapse or reinfection rates. New therapeutic options are urgently needed due to the challenges posed by NTM's ability to form biofilms, unique cell wall structure, and both intrinsic and acquired resistance. Clinical trials for new NTM therapies are limited, and the development of targeted treatments is critical. The current treatment regimen for NTM infections includes antibiotics such as ethambutol, rifampicin, and a macrolide (clarithromycin or azithromycin). However, the effectiveness of these regimens is limited by pharmacokinetic interactions, such as the reduction in macrolide concentrations when used with rifampicin. Additional studies have shown that the addition of liposomal amikacin (LAI) can improve culture conversion rates, though it is associated with significant adverse effects. For Mycobacterium abscessus (MAB), treatment is particularly challenging, with success rates ranging from 41 to 46%. Clinical trials for NTM therapies are limited, with only 58 studies identified on ClinicalTrials.Gov. Most trials focus on new antibiotics as monotherapy or in combination with guideline-based therapy. The inclusion of LAI in treatment regimens has shown improved culture conversion rates, but adverse events remain a concern. New drugs, such as SPR720, are being tested for their potential as novel NTM antibiotics. Antibiotic resistance is a major challenge, with resistance mechanisms including spontaneous mutations and efflux pumps. Biofilms formed by NTMs also complicate treatment, as they are difficult to eradicate. Colony morphology, particularly rough morphology in MAB, is associated with worse treatment outcomes. The unique cell wall structure of NTMs, rich in lipids, contributes to intrinsic resistance and makes them difficult to treat with conventional antibiotics. New treatment options, including repurposed anti-TB drugs like bedaquiline and linezolid, are being explored. Phage therapy has shown promise in treating NTM infections, particularly in combination with antibiotics. However, challenges remain in terms of toxicity, resistance, and the need for personalized treatment approaches. The development of new, more effective therapies is essential to address the growing public health threat posed by NTM infections.Non-tuberculous mycobacteria (NTM) are environmental bacteria that have become increasingly prevalent globally, with rising incidence rates and projected increases without new interventions. Current treatments for NTM infections, particularly for Mycobacterium avium complex (MAC), require a three-drug regimen for about 18 months, with variable success rates and high relapse or reinfection rates. New therapeutic options are urgently needed due to the challenges posed by NTM's ability to form biofilms, unique cell wall structure, and both intrinsic and acquired resistance. Clinical trials for new NTM therapies are limited, and the development of targeted treatments is critical. The current treatment regimen for NTM infections includes antibiotics such as ethambutol, rifampicin, and a macrolide (clarithromycin or azithromycin). However, the effectiveness of these regimens is limited by pharmacokinetic interactions, such as the reduction in macrolide concentrations when used with rifampicin. Additional studies have shown that the addition of liposomal amikacin (LAI) can improve culture conversion rates, though it is associated with significant adverse effects. For Mycobacterium abscessus (MAB), treatment is particularly challenging, with success rates ranging from 41 to 46%. Clinical trials for NTM therapies are limited, with only 58 studies identified on ClinicalTrials.Gov. Most trials focus on new antibiotics as monotherapy or in combination with guideline-based therapy. The inclusion of LAI in treatment regimens has shown improved culture conversion rates, but adverse events remain a concern. New drugs, such as SPR720, are being tested for their potential as novel NTM antibiotics. Antibiotic resistance is a major challenge, with resistance mechanisms including spontaneous mutations and efflux pumps. Biofilms formed by NTMs also complicate treatment, as they are difficult to eradicate. Colony morphology, particularly rough morphology in MAB, is associated with worse treatment outcomes. The unique cell wall structure of NTMs, rich in lipids, contributes to intrinsic resistance and makes them difficult to treat with conventional antibiotics. New treatment options, including repurposed anti-TB drugs like bedaquiline and linezolid, are being explored. Phage therapy has shown promise in treating NTM infections, particularly in combination with antibiotics. However, challenges remain in terms of toxicity, resistance, and the need for personalized treatment approaches. The development of new, more effective therapies is essential to address the growing public health threat posed by NTM infections.