Acquired immune deficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HIV-1), has claimed more than 10 million lives over the past 15 years. There are approximately 30 million HIV-positive people worldwide, 89% of whom reside in sub-Saharan Africa and Asia. The intricate relationship between the virus and HIV-related human multisystem pathology prompted scientists to modify many previously established concepts about infectious diseases and immunology, and to test new ones. The results of this work helped resolve many, albeit not all, long-standing problems concerning HIV-1 immune escape, its cellular tropism, and pathogenesis of HIV-related immunosuppression and nervous system disease. The most impressive advances have been made in antiretroviral drug treatment of HIV infection, which has resulted in dramatically reducing AIDS-related mortality, morbidity, and perinatal transmission. However, considering the magnitude of the worldwide HIV-AIDS pandemic, prohibitive cost and unusually exacting nature of combination drug treatment, as well as the emergence of drug-resistant HIV mutants, the disease and virus remain formidable and unpredictable, particularly in the area of prevention and vaccine development. Here, we have reviewed the most pertinent recently published studies of various aspects of HIV/AIDS intended to answer the following questions: what have we learned and what remains to be determined regarding this unorthodox viral disorder?