This historical review describes the evolution of the pathogenetic concepts associated with infection by the Human Immunodeficiency Virus (HIV), with emphasis on the pathology of the nervous system. Although the first descriptions of damage to the nervous system in the acquired immunodeficiency syndrome (AIDS) only appeared in 1982, the dramatic diffusion of the epidemic worldwide and the invariably rapidly fatal outcome of the disease, before the introduction of efficient treatment, generated from the beginning an enormous amount of research with rethinking on a number of pathogenetic concepts. Less than 25 years after the first autopsy series of AIDS patients were published and the virus responsible for AIDS was identified, satisfactory definition and classification of a number of neuropathological complications of HIV infection have been established, leading to accurate clinical radiological and biological diagnosis of the main neurological complications of the disease, which remain a major cause of disability and death in AIDS patients. Clinical and experimental studies have provided essential insight into the pathogenesis of CNS lesions and natural history of the disease. The relatively recent introduction of highly active antiretroviral therapy (HAART) in 1995-1996 has dramatically improved the course and prognosis of HIV disease. However, there remain a number of unsolved pathogenetic issues, the most puzzling of which remains the precise mechanism of neuronal damage underlying the specific HIV-related cognitive disorders (HIV dementia). In addition, although HAART has changed the course of neurological complications of HIV infection, new issues have emerged such as the lack of improvement or even paradoxical deterioration of the neurological status in treated patients. Interpretation of these latter data remains largely speculative partly because of the small number of neuropathological studies related to the beneficial consequence of this treatment.