HIV-1 infection in children and adolescents can cause progressive neurologic disease, affective brain growth, motor function, and neurodevelopment. In addition, myelopathies, neuropathies, myopathies, strokes, and psychiatric or behavioral manifestations can be a result of HIV-1 infection, OI, or toxicities of treatment interventions. CNS OI are important causes of morbidity and mortality, often mimicking the HIV-1 associated neurologic syndromes. Psychometric, clinical, neuroradiologic, and laboratory testing are valuable for diagnostic and treatment decisions. The cornerstone of treating HIV-1-associated neurologic disease is providing an effective regimen of antiretroviral drugs to reduce the viral burden. It is also necessary to provide rehabilitation, optimize nutrition, supply appropriate antimicrobial prophylaxis against OI, minimize pain, and treat neurobehavioral or psychiatric complications. Efforts at preventing HIV-1 infection are important for diminishing and allaying the growth of this international pandemic.