Human immunodeficiency virus (HIV) infection requires life-long therapy to attain durable suppression of HIV replication and prevent or reverse HIV-related symptoms or immune system dysfunction. Combination therapy with 3 or more antiretroviral medications is currently widely recommended for treatment of children and adolescents with HIV infection. While potent regimens can initially reduce virus load to below assay quantitation limits in the majority of persons with HIV infection, 30% to 80% of children will have regimen failure and return of detectable plasma virus within 1 year. Adherence to therapy is critical to regimen success. Optimal treatment requires careful use of potent combinations of drugs, with attention to adherence, palatability, toxicity, and pharmacokinetics. Practitioners with experience caring for children and adolescents with HIV infection should be involved.