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In France, colorectal cancer (CRC) remains a public health concern due to its high incidence and mortality, primarily caused by its development into incurable metastatic CRC (mCRC). However, the prognosis of CRC has improved in recent years with the advent of therapies targeting the VEGF and EGFR pathways and, more recently, immunotherapy for deficient MisMatch Repair (dMMR) subtypes. The upfront concomitant use of the three cytotoxic agents—5-FU, irinotecan, and oxaliplatin—under the FOLFOXIRI or FOLFIRINOX regimen for unresectable disease is another instance of therapeutic progress. This approach has been show to increase response rates and survival compared to bi-chemotherapy alone. When combined with bevacizumab, it improves all efficacy criteria compared to the same combination with bi-chemotherapy and should now be considered a standard first-line treatment. Conversely, the combination of tri-chemotherapy and anti-EGFR agents provides no additional benefit and should not be used in this context. In addition, intensification of chemotherapy is associated with an increase in side effects, particularly those of a hematologic and gastrointestinal nature. With few exceptions, chemotherapy should not be offered to patients older than 75 years, those with a WHO performance status of ≥2, or those with severe and/or uncontrolled comorbidities. Treatment must also be accompanied by the best possible supportive care (primary prophylaxis with G-CSF for patients over 65, antiemetic prophylaxis adapted to individual risk, etc.) and should be rapidly de-escalated in the event of significant toxicities. The most recent studies published on this topic have attempted to clarify the situations in which tri-chemotherapy plus bevacizumab is most appropriate. Given its high response rate, it should be encouraged as a conversion strategy, especially when the tumor is not a good candidate for bi-chemotherapy plus an anti-EGFR agent. Except in cases where secondary resection is planned, tri-chemotherapy plus bevacizumab is also a good option for mCRC exhibiting poor prognostic factors, including a right-sided primary tumor and/or RAS or BRAFV600E mutations. Finally, this treatment approach is still undergoing investigation, particularly in combination with immunotherapies.