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The introduction of immunotherapy has revolutionized the oncological targeted therapy paradigm. Microsatellite instability (MSI) identifies a subgroup of colorectal cancers (CRCs) which respond to treatment with immune checkpoint inhibitors. Tissue biopsy is currently the gold standard for the assessment of MSI/Mismatch Repair deficiency (MMRd) by means immunohistochemistry or molecular assays. However, the application of liquid biopsy in the clinic may help to overcome several limitations of tissue analysis and may provide great benefit to the diagnostic scenario and therapeutic decision-making process. In the context of MSI/MMRd CRC, the use of liquid biopsy may allow to establish MSI/MMR status if tissue sampling cannot be performed or in case of discordant tissue biopsies. Liquid biopsy may also become a powerful tool to monitor treatment response and the onset resistance to immunotherapy over time and to stratify of MSI/MMRd patients according to their risk of relapse and metastases. The aim of this review is to summarize the main technical aspects and clinical applications, the benefits, and limitations of the use of liquid biopsy in MSI/MMRd colorectal cancer patients., Competing Interests: UM has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, ThermoFisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck, and AstraZeneca, Jannseen unrelated to the current work. SL has received personal fees for consulting or advisory role from Amgen, Merck Serono, Lilly, Astra Zeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, MSD, Roche, Pierre-Fabre, and GSK, and receiving research grants from Amgen, Merck Serono, Bayer, Roche, Lilly, Astra Zeneca, and Bristol-Myers Squibb, unrelated to the current work. Matteo Fassan received research funding from Astellas Pharma, Macrophage Pharma and QED Therapeutics and had roles as consultant or advisor for Astellas Pharma, Roche, Astra Zeneca, MSD and GSK-Tesaro, unrelated to the current work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ceccon, Angerilli, Rasola, Procaccio, Sabbadin, Bergamo, Malapelle, Lonardi and Fassan.)