In the absence of antiretroviral treatment, HIV-1 establishes a chronic, progressive infection of the human immune system that invariably, over the course of years, leads to its destruction and fatal immunodeficiency. Paradoxically, while viral replication is extensive throughout the course of infection, deterioration of conventional measures of immunity is slow, including the characteristic loss of CD4⁺ T cells that is thought to play a key role in the development of immunodeficiency. This conundrum suggests that CD4⁺ T cell–directed viral cytopathicity alone cannot explain the course of disease. Indeed, recent advances now indicate that HIV-1 pathogenesis is likely to result from a complex interplay between the virus and the immune system, particularly the mechanisms responsible for T cell homeostasis and regeneration. We review these data and present a model of HIV-1 pathogenesis in which the protracted loss of CD4⁺ T cells results from early viral destruction of selected memory T cell populations, followed by a combination of profound increases in overall memory T cell turnover, damage to the thymus and other lymphoid tissues, and physiological limitations in peripheral CD4⁺ T cell renewal.