Many questions have been posed about acquired immunodeficiency syndrome (AIDS) pathogenesis. Is human immunodeficiency virus (HIV) both necessary and sufficient to cause AIDS? Is AIDS essentially an autoimmune disease, triggering apoptosis, or is virus infection the cause of T helper lymphocyte depletion? What is the significance of HIV tropism and the role of macrophages and dendritic cells in AIDS? Is there viral latency and why is there usually a long period between infection and AIDS? Is HIV variation a crucial aspect of its pathogenesis and, if so, do virulent strains emerge? Although this article provides few definitive answers, it aims to focus commentary on salient points. Overall, it is increasingly evident that both the tropism and burden of HIV infection correlate closely with the manifestations of disease.