The combination of three or more antiretroviral drugs is referred to as highly active antiretroviral therapy (HAART) and constitutes the standard of care for HIV-1 patients in industrialized nations. Although HAART is usually effective in reducing viral load and re-constituting CD4 counts, latent virus reservoirs persist, and as many as 60 years therapy [1, 2] may be required to eradicate the virus. Meanwhile, patients are likely to experience drug related toxicity and may have to change therapy due to the emergence of drug resistant strains. For these reasons, the search for different therapeutic approaches continues. A new concept of antiviral / cytostatic (“virostatics”) drugs has been proposed within the context of HAART to restrict virus target populations (CD4+ T lymphocytes), target viral reservoirs, and possibly restore immune functions, by reducing excess immune activation, a fundamental component of HIV / AIDS pathogenesis. These virostatics include drugs such as hydroxyurea, mycophenolic acid, leflunomide and rapamycin, which are currently used for other therapeutic indications; and other expe rimental drugs, which are not for human use. They utilize multiple novel mechanisms of action to impede HIV by targeting host cellular proteins that are not susceptible to mutation. Therefore, their resistance profile appears to be quite favorable. Since many of these drugs act by inhibiting the synthesis of deoxynucleotides, essential for HIV reverse transcription, they favor the incorporation of nucleoside analogues into viral DNA, thus synergizing with the antiviral activity of currently used nucleoside reverse transcriptase inhibitors (NRTI). The rationale for the use of virostatics in HIV / AIDS, their mechanism of action, and ongoing preclinical and clinical research will be reviewed.