Given the long-term clinical latency and high level of replication of human immunodeficiency virus (HIV), it is not surprising that HIV has developed a method of persistence involving production of novel variants in its proteins. Therapeutic vaccines attempt to harness enhanced immune mechanisms to control viral replication, and thus prevent disease progression. A major problem in the development of a vaccine is the great variety of viral quasispecies in HIV infection worldwide and within the lifetime of a given individual. Furthermore, the protective immune parameters that correlate with the ability to control disease progression remain undefined. Manufacturers have followed a number of paths to select an immunogen. At present, investigators are monitoring different immune and viral parameters to measure the effects of therapeutic vaccination. This monitoring ranges from HIV-specific cellular and humoral immunity to viral load markers and skin tests to recall antigens. Two possible major limitations to this treatment approach are the declining potency of the immune response and the ability of the virus to produce escape mutants, particularly during disease progression as viral replication increases. The latter escape mechanism could be similar to the specific pol mutations that enable the virus to escape the impact of drug therapy. Although apparent safety has been observed in phase II/III studies using several HIV envelope-based therapeutic vaccines, investigators have documented reproducible immunogenicity only in HIV-seropositive individuals with CD4+ T cells > 400/mm3. A convincing impact of vaccine therapy on viral load or the course of HIV disease has not been demonstrated.