The biologically active form of most purine or pyrimidine analogs is the nucleoside 5'-mono, di- or triphosphate. The nucleoside form is most often administered because of the ease with which it penetrates cells by facilitated transport. However, many nucleoside derivatives fail to exhibit significant antiviral or antitumor activity because they are not phosphorylated by cellular enzymes to the active nucleotide form. In this review, the potential use of suitable nucleotide analogs as selective inhibitors of ribonucleotide reductase and viral reverse transcriptase is considered. Masked nucleotides such as phosphoramidates or methyl phosphates could be employed to allow transport across cellular membranes. Furthermore, phosphonocarboxamide, phosphonoformate or sulfamidophosphoramidate may mimic nucleotide di- and triphosphates. Tumor cells and virally infected cells are often more permeable to nucleotides and their analogs than normal cells, which could provide a therapeutic advantage. There could be considerable therapeutic potential for nucleotide analogs that can penetrate the tumor cell membranes and that are resistant to enzymatic hydrolysis and are non-incorporable into DNA or RNA.