Abstract: The use of nucleoside analogues as antiviral agents is expanding. For most nucleoside analogues, intracellular phosphorylation is the major prerequisite for activity. Antiviral activity may be limited by poor uptake, absence of appropriate activating enzymes, catabolism, and competition from endogenous nucleotides. Appreciation of these factors, which are species-, tissue- and cell-specific is important in the understanding of the pharmacology and toxicology of nucleoside analogues. The use of nucleoside analogues against the agents of viral hepatitis is inherently problematic for many reasons including active hepatic nucleoside catabolism, probable absence of virus-specific activating enzymes, competition from endogenous nucleotides synthesised de novo or derived from RNA turnover, and factors related to mitochondrial toxicity. Despite these drawbacks, some nucleoside analogues have been found efficacious against hepatitis B virus and it is likely that as knowledge of their mechanism of action accumulates, their efficacy can be improved both by rational drug design and by use in combination with other drugs, including interferon.