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The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.