One of the most widely used drugs in cancer chemotherapy is 5-fluorouracil (5-FU). 5-FU is optimally delivered via continuous iv. infusion, which is both cumbersome and expensive. Prolonged oral dosing of 5-FU could mimic continuous infusion with less inconvenience and cost. However, oral administration of 5-FU has been hampered by incomplete and erratic bioavailability due to substantial variability in the activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism. Eniluracil (ethynyluracil, GlaxoWellcome, USA), a uracil analogue, which irreversibly inhibits DPD, increases the oral bioavailability of 5-FU to 100%, facilitating uniform absorption and predictable toxicity. Cytotoxicity is enhanced one- to five-fold in cell lines treated with eniluracil plus 5-FU compared with 5-FU alone. Though eniluracil is neither toxic nor active as a single agent in animals, it improves the antitumour efficacy and therapeutic index of 5-FU. In Phase I trials, eniluracil markedly reduced the maximum tolerated dose of oral 5-FU, increased the half-life 20-fold and decreased the clearance 22-fold. DPD is completely inactivated within 1 h of eniluracil administration. Two dosing schedules have been evaluated in combination with oral 5-FU: a 5-day schedule every 28 days and a 28-day schedule every 35 days. The dose-limiting toxicity on the first schedule is myelosuppression with diarrhoea being dose-limiting on the 28-day schedule. Phase II trials employing the 28-day schedule have been completed in cancers of the colon, breast, liver and pancreas. Phase III trials in colorectal and pancreatic carcinoma have been completed and await analysis. Eniluracil is a promising drug, which permits reliable and safe administration of oral 5-FU and has the potential to overcome 5-FU resistance mediated by overexpression of DPD.