The standard treatment for patients with metastatic colorectal cancer (mCRC) in the first- and second-line setting is generally chemotherapy, which can be augmented with vascular endothelial growth factor-targeted therapies and, for patients with KRAS wild-type status, epidermal growth factor receptor-targeted therapies. However, nearly all patients ultimately develop disease progression and require later lines of therapy. Traditionally, physicians recycled chemotherapy in the later lines, with many patients showing diminished or no response. However, the past several years have seen the introduction of 2 agents for patients with refractory mCRC entering the third-line setting. The multitargeted tyrosine kinase inhibitor regorafenib and the cytotoxic combination of trifluridine/tipiracil have demonstrated significant improvements in overall survival in patients with refractory mCRC. Although these agents do not seem to induce complete responses, they can lead to durable stable disease. Regorafenib and trifluridine/tipiracil differ in their safety profiles. Physicians and patients must be properly educated on how to recognize and mitigate adverse events. For regorafenib, a dose-escalating strategy improves tolerability without impacting efficacy. When sequencing these agents, physicians should consider patient characteristics, including comorbidities, prior adverse reactions to treatments, and overall performance status. Ongoing studies are further defining the role of regorafenib and trifluridine/tipiracil in the treatment of mCRC.