Sorivudine provides a unique nucleoside analog with significantly enhanced both in vitro and in vitro activity and enhanced oral bioavailability. Early indications from controlled studies indicate that sorivudine therapy is superior to acyclovir for the treatment of localized zoster in individuals with HIV infection and adults with chicken pox. However, these studies await peer evaluation. Importantly, recent experience in Japan indicates administration of sorivudine with 5-fluorouracil (5-FU) is contraindicated. Sorivudine inhibits dihydropyrimidine dehydrogenase, which is required for the metabolism of 5-FU. As a consequence, toxic levels of 5-FU accumulate in the plasma and have led to the deaths of nearly 30 patients in Japan. One might question, as these data unfold, the relative value of drugs with such enhanced in vitro activity and oral bioavailability as compared with standard therapeutic agents. Should accelerated healing occur, but not as dramatically as would have been anticipated from the in vitro data, unique approaches to the management of herpes zoster will need to be developed if further improvement is desired. Regardless, sorivudine appears superior to acyclovir for acceleration of cutaneous healing and, importantly, can be administered once daily in significantly smaller concentrations. These findings in and of themselves should allow for licensure of the compound in other developed societies.