Colorectal cancer is the second leading cause of cancer death in the USA and fluoropyrimidines have been the mainstay of treatment for over 40 years. Currently, capecitabine is the only orally available fluoropyrimidine approved for treatment in the USA. As a single agent it has demonstrated activity and equivalence to 5-fluorouracil (5-FU) intravenous administration via the Mayo Clinic regimen, in both the metastatic and adjuvant settings. Ongoing clinical trials are evaluating the efficacy of capecitabine in combination with oxaliplatin and irinotecan as more convenient substitutes for infusional 5-FU in the 5-FU/leucovorin/oxaliplatin and 5-FU/irinotecan regimens.