Trifluridine/tipiracil (TAS-102) is a new oral combination therapy approved by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer who are refractory to or intolerant of standard chemotherapy. This agent consists of a thymidine-based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil), which is included to reduce the degradative breakdown of trifluridine. In the phase III Randomized, double-blind, phase III Study of TAS-102 plus best supportive care [BSC] versus placebo plus BSC in patients with metastatic colorectal cancer [CRC] refractory to standard chemotherapies (RECOURSE) trial, trifluridine/tipiracil showed significant improvement in overall survival compared with placebo. Trifluridine/tipiracil is administered at a 35 mg/m2 dose orally twice daily in a 28-day cycle consisting of 5 treatment days/2 rest days for 2 weeks followed by a rest period of 2 weeks. Because trifluridine/tipiracil is a completely oral chemotherapy regimen, patient adherence to treatment is an important consideration. It is also critical to have strategies in place for managing toxicities, because side effects might have a negative effect on patient adherence. The most frequent adverse events reported in patients with metastatic colorectal cancer receiving trifluridine/tipiracil in the phase III RECOURSE trial were myelosuppression, nausea/vomiting, diarrhea, decreased appetite, and fatigue. In this review we aim to provide clinicians with practical recommendations for facilitating patient adherence to oral chemotherapy, managing trifluridine/tipiracil dosing, and address the most common adverse events in patients who receive trifluridine/tipiracil therapy.