Antiretroviral therapy in children has expanded dramatically in low-income and middle-income countries. The World Health Organization revised its pediatric HIV guidelines to recommend initiation of antiretroviral therapy in all HIV-infected children younger than 2 years, regardless of CD4 count or clinical stage. The number of children starting life-long antiretroviral therapy should therefore expand dramatically over time. The early initiation of antiretroviral therapy has indisputable benefits for children, but there is a paucity of definitive information on the potential adverse effects. In this review, a comprehensive literature search was conducted to provide an overview of our knowledge about the complications of treating pediatric HIV. Antiretroviral therapy in children, as in adults, is associated with enhanced survival, reduction in opportunistic infections, improved growth and neurocognitive function, and better quality of life. Despite antiretroviral therapy, HIV-infected children may continue to lag behind their uninfected peers in growth and development. In addition, epidemic concurrent conditions, such as tuberculosis, malaria, and malnutrition, can combine with HIV to yield more rapid disease progression and poor treatment outcomes. Additional studies are required to evaluate the long-term effects of antiretroviral therapy in HIV-infected infants, children, and adolescents, particularly in resource-limited countries where concomitant infections and conditions may enhance the risk of adverse effects. There is an urgent need to evaluate drug-drug interactions in children to determine optimal treatment regimens for both HIV and coinfections.