Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil (5-FU) delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption, dosage reduction, or, even, therapy discontinuation for patients on a capecitabine regimen. Interestingly, addition of a dihydropyrimidine dehydrogenase (DPD) inhibitor, such as uracil, 5-chloro-2,4-dihydroxypyridine, or eniluracil, to the fluoropyrimidine treatment regimen significantly diminishes the incidence of HFS. DPD inhibitors were initially combined with fluoropyrimidines to increase the efficacy of the drugs by impairing the DPD-mediated catabolism of 5-FU. However, with the accumulating findings from clinical trials that show the benefits of DPD inhibition on decreasing the risk of HFS, consideration should be given to changing the recommendations for the treatment of cancer patients with fluoropyrimidines to include DPD inhibitor components as standard therapy.