2’,3’-Dideoxynucleosides currently represent the major chemotherapeutic agents in the treatment and prevention of AIDS. These nucleoside analogues have no intrinsic activity against HIV and must be metabolized to their respective 5’-triphosphate by means of kinases, nucleotidases, or other activating enzymes present naturally in cells. With regard to this metabolism, each 2’,3,-dideoxynucleoside constitutes a unique entity with specific cellular and molecular properties. It has been shown that the antiretroviral activity of some of them could be enhanced by using their nucleotide prodrugs (« Pronucleotides ») which are able to deliver the corresponding nucleoside 5’-monophosphate analogue in infected cells. In this respect, recent examples of pronucleotides that display in vitro anti-HIV activity include mononucleoside phosphotriesters incorporating enzyme-labile transient phosphate-protecting groups. Among them, phosphotriesters bearing S-acyl-2-thioethyl (SATE) groups as biolabile phosphate protections emerged as promising new kinds of esterase-labile pronucleotides. Here, on the basis of two 2’,3’-dideoxynucleoside models (namely, AZT and ddU), we reviewed physical and biological properties of the corresponding bis(SATE) phosphotriesters. Thus, in vitro anti-HIV-1 activities of these pronucleotides in several cell types (including human peripheral-blood mononuclear cells and monocyte-derived macrophages) are discussed in relation to their lipophilicity and stability in cells extracts and culture medium. Currently, our research group is considering an in vivo implementation of the SATE pronucleotide approach, and preliminary experiments on the chemical and enzymatical stabilities of SATE pronucleotides in human biological media are presented.