There are approximately 56 million people who harbor Mycobacterium tuberculosis that may progress to active tuberculosis (TB) at some point in their lives. Modeling studies suggest that if only 8% of these individuals with latent TB infection (LTBI) were treated annually, overall global incidence would be 14-fold lower by 2050 compared to incidence in 2013, even in the absence of additional TB control measures. This highlights the importance of identifying and treating latently infected individuals, and that this intervention must be scaled up to achieve the goals of the Global End TB Strategy. The efficacy of LTBI treatment is well established, and the most commonly used regimen is 9 months of daily self-administered isoniazid. However, its use has been hindered by limited provider awareness of the benefits, concern about potential side effects such as hepatotoxicity, and low rates of treatment completion. There is increasing evidence that shorter rifamycin-based regimens are as effective, better tolerated, and more likely to be completed compared to isoniazid. Such regimens include four months of daily self-administered rifampin monotherapy, three months of once weekly directly observed isoniazid-rifapentine, and three months of daily self-administered isoniazid-rifampin. The success of LTBI treatment to prevent additional TB disease relies upon choosing an appropriate regimen individualized to the patient, monitoring for potential adverse clinical events, and utilizing strategies to promote adherence. Safer, more cost-effective, and more easily completed regimens are needed and should be combined with interventions to better identify, engage, and retain high-risk individuals across the cascade from diagnosis through treatment completion of LTBI.