One of the greatest achievements of biomedical research has been the use of combined highly active antiretroviral therapy (HAART) for the treatment of HIV-infected patients. The profound decrease in viral multiplication obtained by a combination of reverse transcriptase and protease inhibitors results in partial restoration of the immune system, sufficient to prevent most opportunistic infections and cancers, and therefore to maintain HIV-infected patients in a relatively good condition. However, no complete cure has been achieved with any of the combined treatments. Despite the fact that viral RNA in the plasma can be reduced to levels that are undetectable by most sensitive molecular techniques, there remains a fraction of the virus population apparently insensitive to retroviral inhibitors. When treatment is interrupted, virus multiplication resumes and within weeks reaches the initial level that existed before the treatment. The nature of the viral reservoir at the origin of this rebound is a matter of discussion. It could come from long-lived cells where viral DNA has integrated, such as dormant stem cells, or from cells or tissues poorly accessible to antiviral drugs. By centrifuging plasma from patients under treatment over a sucrose density gradient, we have been able to detect infectious particles, despite the fact that such particles were not detected by sensitive molecular techniques measuring viral load. Moreover, such patients exhibit signs of residual disease: the number of CD4 T cells and the ratio of CD4 to CD8 cells never reaches the normal values observed in HIVnegative patients, even after years of antiretroviral treatment. Ex vivo, we can detect abnormal activation of macrophages, as evidenced by the over-expression of fas ligand. At the clinical level, long-term treatment results in serious side effects (perturbation of lipid metabolism leading to cardiovascular problems), and in the emergence of drug-resistant viral mutants, not to mention the abyssal cost of such treatment. Therefore, there is a strong need for additional therapy aimed at a functional – not necessarily physical – eradication of the viral infection, so that treatment duration will be limited. The pharmaceutical industry is engaged in the design and commercialization of new types of viral inhibitors, acting on new targets of the viral multiplication cycle: inhibitors of the viral integrase, of the binding of virus to cellular receptors, or of the fusion of the viral membrane to the plasma membrane. Although this new generation of drugs could be expected to provide a better suppression of viral multiplication and an efficient treatment for patients infected with viruses resistant to classical inhibitors, it is unlikely that, alone, they will achieve viral eradication.