Long-acting injectable antiretroviral therapy (LA ART) has been found to be non-inferior to daily oral ART in phase 3 clinical trials and is poised to soon enter routine clinical care. This treatment modality has the potential to address many barriers to daily oral ART adherence among people living with human immunodeficiency virus (HIV) and for HIV Pre-Exposure prevention. Data from the Patient Reported Outcomes (PROs) showed high rates of satisfaction, acceptability, tolerability and preference for the LA regimen, compared with the daily oral treatment. Once LA ART is available, access and uptake will be limited because of current knowledge gaps in the use of these agents and multiple challenges many specific to low-income and middle-income countries, where the epidemic is most concentrated and HIV prevention and treatment options are limited. These gaps will lead to multiple systems-level and individual-level barriers to implementation. Anticipating and addressing these gaps and barriers will help fulfill the promise of these agents against the pandemic.