Non-tuberculous mycobacteria (NTM) are opportunistic environmental bacteria that are increasingly prevalent globally. Effective treatments for NTM infections remain suboptimal, with standard therapy for *Mycobacterium avium* complex (MAC), the most commonly isolated NTM, requiring a 3-drug regimen over 18 months, achieving culture conversion rates between 45% and 70%, and high relapse or reinfection rates of up to 60%. New therapeutic options are urgently needed. Clinical trials listed on ClinicalTrials.Gov for new NTM therapies show that most involve dose and combination therapy of guideline-based treatments or include additional drugs such as Amikacin, Clofazimine, Azithromycin, Bedaquiline, and Linezolid. The challenges in developing new treatments include the ability of NTMs to form biofilms, their unique cell wall structure, and intrinsic and acquired resistance. Increased investment in targeted treatments for NTM infections is essential. The review highlights the significant challenges in NTM treatment, including limited clinical trials, drug discovery pipelines, and resistance, and discusses opportunities for new therapeutics.Non-tuberculous mycobacteria (NTM) are opportunistic environmental bacteria that are increasingly prevalent globally. Effective treatments for NTM infections remain suboptimal, with standard therapy for *Mycobacterium avium* complex (MAC), the most commonly isolated NTM, requiring a 3-drug regimen over 18 months, achieving culture conversion rates between 45% and 70%, and high relapse or reinfection rates of up to 60%. New therapeutic options are urgently needed. Clinical trials listed on ClinicalTrials.Gov for new NTM therapies show that most involve dose and combination therapy of guideline-based treatments or include additional drugs such as Amikacin, Clofazimine, Azithromycin, Bedaquiline, and Linezolid. The challenges in developing new treatments include the ability of NTMs to form biofilms, their unique cell wall structure, and intrinsic and acquired resistance. Increased investment in targeted treatments for NTM infections is essential. The review highlights the significant challenges in NTM treatment, including limited clinical trials, drug discovery pipelines, and resistance, and discusses opportunities for new therapeutics.