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Immunotherapy has recently become a major treatment modality for several types of solid tumours, achieving remarkable and long-lasting remissions. In metastatic colorectal cancer patients (mCRC), immune checkpoint inhibitors (ICIs) were found to be effective as treatment for deficient mismatch repair (dMMR)/ microsatellite instability high (MSI-H) tumours and received regulatory approval for this indication. However, mCRC is a complex disease and dMMR/MSI-H tumours represent a minority of the cases; therefore, new strategies are needed to extend the benefits of immunotherapy to a larger population of patients. This review explores the immunological differences between dMMR/MSI-H and proficient mismatch repair (pMMR)/ microsatellite instability low (MSI-L) tumours, focuses on new proposed biomarkers to predict response to immunotherapy and illustrates results reported from the main clinical trials with immunotherapeutic agents in CRC, addressing the most promising approaches being currently developed.