Until recently, treatment options for patients with metastatic colorectal cancer (CRC) were limited to chemotherapy, vascular endothelial growth factor–targeted therapy, and, for patients with RAS-wild type tumors, epidermal growth factor receptor–targeted therapy. For patients with disease progression after treatment, newer agents are now available: the multitargeted tyrosine kinase inhibitor regorafenib and the cytotoxic combination of trifluridine and tipiracil (TAS-102). Both regorafenib and trifluridine/tipiracil have demonstrated significant improvements in overall survival in patients with refractory metastatic CRC. Durable responses exceeding a year have been reported with regorafenib. The agents differ in their safety profiles. Regorafenib is associated with hand-foot skin reaction and fatigue, primarily in the first cycle. Alternative dosing strategies appear to improve the tolerability of regorafenib, and randomized dosing studies are underway to define the optimal strategy. Trifluridine/tipiracil is associated primarily with myelosuppression. Sequencing of these agents can be guided by patient characteristics, such as comorbidities and adverse reactions to previous treatments. Patients with a poor performance status are not likely to benefit from regorafenib. Ongoing studies are further defining the role of regorafenib and trifluridine/tipiracil in the treatment of metastatic CRC.