Infection with HIV-1 has spread exponentially in recent years to reach alarming proportions. It is estimated than more than 33 million adults and 1.3 million children are infected worldwide. Approximately 16,000 new cases are diagnosed every day and almost 3 million people die every year from AIDS, making it the fourth leading cause of death in the world. Since the introduction of highly active anti-retroviral therapy (HAART) in the mid 1990s, the morbidity and mortality associated with HIV-1 infection has significantly decreased and AIDS has become a chronic disorder. However, neuropathological conditions associated with AIDS are still present in approximately 70 to 90% of patients and can be the result of HIV itself or of opportunistic infections. Here we briefly review the pathology and pathophysiology of AIDS-Encephalopathy, of some of the significant opportunistic infections affecting the brain in the context of AIDS, including Progressive Multifocal Leukoencephalopathy (PML) a demyelinating disease caused by the human neurotropic JC virus, Toxoplasmosis, Cryptococcosis and of primary CNS lymphoma, a brain malignancy frequently associated with HIV-1 infection, all of them considered AIDS defining conditions.