A summary of the most recent advances to the design of pronucleotides will be presented. Approaches that have been designed to be activated by enzymes such as carboxyesterases [bis(POM)-, bis(POC)-, bis(SATE)-, bis(AB) phosphotriesters and the arylphosphoramidates] or by reductases [bis(SDTE) approach] will be discussed as well as the amino acids phosphoramidate diester concept with its still unknown delivery mechanism and the cycloSal approach that releases the nucleotides by an induced tandem reaction.Nucleoside analogues, e.g. 2',3'-dideoxy-2',3'-didehydrothymidine 1 (d4T), 3'-azido-2',3'-dideoxythymidine 2 (AZT) or 5-fluoro-2'-deoxyuridine 3 (5-FdU), are structurally different as compared to the corresponding natural DNA or RNA nucleosides with regard to modification of the glycon as well as the aglycon residue. Due to this modified structure, these compounds are widely used as antiviral or antitumor drugs in chemotherapy ( Figure 1) (1) . Since the discovery of AZT 2 as the first nucleoside drug for the treatment of AIDS, considerable efforts have been made to develop new nucleoside analogues that would be more active, less toxic inhibitors of the HIV-1 reverse transcriptase (RT) (2) . The general mode of action of nucleoside analogues is the inhibition of the HIV-1 RT by acting as competitive inhibitors or as DNA chain terminators. To act as DNA chain termination agents or RT inhibitors, intracellular conversion of the nucleoside analogues into their 5'-mono-, 5'-di-or 5'-triphosphates is a prerequisite after cell penetration (3) . The enormous disparity in anti-HIV activity that is evident for a large number of dideoxynucleoside analogues belies their apparent structural similarity. Due to these structural differences as compared to natural nucleosides the metabolization to the corresponding dideoxynucleoside triphosphates is often inefficient and consequently the therapeutic efficacy is sometimes limited (4) . For example, in the case of the anti-HIV active dideoxynucleoside analogue d4T 1 (Stavudine, Zerit ® ) (5) the first phosphorylation to d4T 5'-monophosphate 4 catalyzed by thymidine kinase (TK) is the rate-limiting step in human cells (6) . More striking, however is 2',3'-dideoxyuridine triphosphate (ddUTP) which is one of the most powerful and selective inhibitors of HIV reverse transcriptase (K i = 0.05 µM) while the parent nucleoside 2',3'-dideoxyuridine 5 (ddU) is virtually ineffective at blocking HIV infection in cultured cells. Biochemical and pharmacological studies in three different human T cell lines (CEM, showed that ddU 5 itself was not anabolized to the 5'-monophosphate, most apparently because it was a poor substrate for cellular nucleoside kinases because of the considerable substrate specificity of these enzymes (7) . In contrast, in a few cases the limited efficacy is also due to a catabolic enzymatic reaction. For example, 2',3'-dideoxyadenosine 6 (ddA) is rapidly intracellularly deaminated to ddI 7 by adenosine deaminase (ADA) (8,9) . As a consequence, ddI 7 has to ...