The scale-up of pediatric antiretroviral therapy (ART) in sub-Saharan Africa over the past decade involved unprecedented political and donor commitment. These pediatric ART programs have demonstrated they can provide ART to human immunodeficiency virus (HIV)-infected children and that these children achieve treatment outcomes comparable to children in high-resource settings. Several obstacles, however, have hindered program implementation and impacted treatment outcomes. Challenges particularly affecting children include shortages of properly trained healthcare providers, lack of laboratory capacity for infant diagnosis and pediatric treatment monitoring, poor adherence, disclosure of HIV infection status and attrition. Innovative solutions to these challenges have been developed and programs are demonstrating they can successfully expand services to increase ART coverage in affected communities. As programs optimize the care and treatment of children, and more efficiently provide HIV services within the health care system, new challenges arise, including integration of child and family health services, use of electronic health records and the potential need for rationing antiretroviral drugs. Further evaluation of innovative solutions to these challenges and barriers to care, as well as continued commitment on the part of governments and donors, will be required if all HIV-infected children are to receive proper care.