Many nucleoside analogues such as azt, ddI, ddC, d4T, 3TC, acv and vacv are currently being used in the treatment of patients infected with HIV, suffering from AIDS, or AIDS-related opportunistic infections. The transport of nucleoside analogues across the gastrointestinal tract is mediated by a number of transporters that fall into three broad categories, i.e., Na(+)-dependent concentrative transporters, Na(+)-independent equilibrative transporters and H(+)/peptide transporters. The first two transporter classes contain a large number of subtypes that are based on the substrate specificity. Recent studies have shown that most of the anti-HIV nucleoside analogues are transported by one or more of the nucleoside transporters. Furthermore, certain analogues, such as acv, appear to be absorbed by non-carrier-mediated diffusion, whereas vacv is apparently transported by non-nucleoside transporters (e.g., the oligopeptide transporter, PepT1 and possibly others). Thus, it is desirable to understand the precise nature of the absorption mechanism of these drugs to improve bioavailability and reduce the variability that is commonly observed in vivo in human patients. A complete understanding of the complex interactions of nucleoside analogues with the various transporters will help in designing better delivery systems and strategies to improve efficacy. In the current report, the mechanisms of nucleoside and nucleoside-analogue transport are reviewed. Also, methods of exploiting prodrugs to improve the bioavailability characteristics of drugs are highlighted.