5-Fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy is used in rectal cancer to prolong survival, downsize tumors prior to surgery, and allow for sphincter-sparing surgery. Capecitabine is an oral fluoropyrimidine that generates 5-FU preferentially within the tumor. It has been shown to be as effective as 5-FU and well tolerated in the metastatic and adjuvant settings in colorectal cancer. Capecitabine is more convenient for patients than 5-FU, and it avoids the risks of infection and thromboembolism associated with intravenous administration. It was also shown to reduce the use of medical resources, healthcare professionals' time, and cost of therapy. Emerging data from Phase II trials of neoadjuvant regimens in which capecitabine has been substituted for 5-FU are encouraging.