In recent years, major advances have been made in the care of HIV-infected children, particularly in antiretroviral treatment, which have dramatically improved survival and quality of life. The goal of highly active antiretroviral therapy (HAART), which includes at least three potent drugs, is the maximal and most durable suppression of viral replication possible, which is often not achieved despite clear immunologic and clinical improvement. There are still major barriers to achieving this goal, mainly the difficulty of permanent adherence to complex regimens and treatment-related toxicities. Adverse events are frequent, including a high prevalence of metabolic complications with unknown consequences in the future. These drawbacks of antiretroviral treatment are leading to a more conservative initial approach, as well as to research into simpler and less toxic therapeutic options. New strategies should continue to be developed to overcome the still important limitations of current antiretroviral treatment.