Fluorouracil (FU) is essentially eliminated in the liver through the rate limiting enzyme dihydropyrimidine dehydrogenase (DPD). DPD is also expressed in various other normal as well as in tumor tissues. DPD activity measured in peripheral blood mononuclear cells (PBMC) is correlated to FU systemic clearance, but this correlation is weak, precluding PBMC-DPD to be considered as a reliable predictor of FU clearance. Nevertheless, patients with suspected or proven PBMC-DPD deficiency exhibit severe FU-related toxicities. Population studies performed so far were unable to detect complete DPD deficient patients, suggesting that complete DPD deficiency is a very rare event; however 3% of patients exhibit a partial DPD deficiency indicative of increased risk for developing FU-related toxicity. Although FU resistance is multifactorial, DPD activity in tumor cells (in vitro and clinical studies) is significantly related to FU sensitivity: the lower the DPD activity, the greater the FU efficacy. Further prospective clinical studies will be required in order to confirm the present observations.