In this paper Zeda Rosenberg and Anthony Fauci review the prevailing hypotheses on the mechanisms by which human immunodeficiency virus (HIV) progressively and relentlessly destroys immune function in infected individuals. Although HIV can directly kill CD4+ T cells in vitro, the protracted course of HIV infection in vivo suggests that other pathogenic mechanisms are also involved. As a member of the lentivirus family, HIV can remain latent within the genome of the infected cell. Activation of HIV expression from a latent or low-level state of replication is dependent, in part, on the state of activation of the host cell. As a result, activation of HIV-infected CD4+ T cells or monocyte/macrophages during normal immune responses may ultimately result in the activation of HIV expression and spread of the infection. Thus, HIV may have developed the ability to use normal immune processes to its own reproductive advantage.