Human immunodeficiency virus (HIV) infection is generally characterized by inefficient viral transmission; an acute phase of intense viral replication and dissemination to lymphoid tissues; a chronic, often asymptomatic phase of sustained immune activation and viral replication; and an advanced phase of marked depletion of CD4⁺ T cells that leads to acquired immune deficiency syndrome. Major insight into HIV transmission and each phase of infection has been gained from studies on blood and tissue specimens obtained from HIV-infected individuals, as well as from animal and ex vivo models. Not only has the introduction of effective antiretroviral therapy greatly diminished the morbidity and mortality associated with HIV disease progression, it has also provided new avenues of research toward delineating the mechanisms of HIV-induced pathogenesis. Further advances in therapeutics and informative technologies, combined with a better understanding of the immunologic and virologic components of HIV disease, hold promise for new preventative and even curative strategies.