Trifluridine-tipiracil is an oral combination product containing the thymidine analog, trifluridine, along with a thymidine phosphorylase inhibitor, tipiracil, which inhibits the degradation of trifluridine. Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Trifluridine-tipiracil has an indication for the treatment of gastric adenocarcinoma and cancer of the gastroesophageal junction. It is also indicated for metastatic colorectal cancer that has been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF targeted agent, and if RAS wild-type, an anti-EGFR therapy. Anti-VEGF and anti-EGFR therapies will be discussed in the next Chapter. In a trial conducted in patients with mCRC who had progressed through at least two prior regimens, trifluridine-tipiracil was associated with a significant improvement in overall survival and improved progression-free survival compared to placebo. The most common adverse events were neutropenia, leukopenia, and febrile neutropenia. Trifluridine-tipiracil is currently considered a treatment option for patients who have progressed through all other available regimens.