In contrast to most animal viruses, infection with the human and simian immunodeficiency viruses results in prolonged, continuous viral replication in the infected host. Remarkably, viral persistence is not thwarted by the presence of apparently vigorous, virus-specific immune responses. Several factors are thought to contribute to persistent viral replication, most notably the destruction of virus-specific T helper cells, the emergence of antigenic escape variants, and the expression of an envelope complex that structurally minimizes antibody access to conserved epitopes. Not as well understood, though potentially important, is the ability of at least one viral encoded protein (Nef) to prevent presentation of viral antigens in the context of major histocompatibility complex. The future success of antiviral therapies and vaccination strategies may depend largely on understanding how and to what degree each of these factors (and presumably others) contributes to immune evasion.