Microsatellite instability (MSI-H) is a key feature in colorectal cancer (CRC) development, occurring in 15% of cases. It is characterized by mutations in microsatellite sequences due to defects in the mismatch repair (MMR) system, primarily involving MSH2, MLH1, and MSH6 proteins. MSI-H is associated with a better prognosis and can predict the effectiveness of chemotherapy in CRC. However, clinical trials have shown conflicting results regarding its predictive value for treatment response. MSI-H tumors are often located proximally in the colon, are poorly differentiated, and have a higher lymphocytic infiltration. They are less likely to metastasize and have a better prognosis compared to microsatellite stable (MSS) tumors. MSI-H tumors are resistant to 5-fluorouracil (5-FU) chemotherapy but more sensitive to irinotecan and oxaliplatin. Recent meta-analyses suggest that MSI-H patients have better survival rates, but there is inconsistency in the effectiveness of 5-FU-based chemotherapy. The future of CRC treatment lies in personalized therapy based on molecular characteristics, including MSI-H status. MSI-H is a significant prognostic and predictive factor in CRC, and its identification can guide treatment decisions. A prognostic model has been developed to predict MSI-H status based on clinical and pathological features, improving cost-effectiveness in diagnosis. Overall, MSI-H plays a crucial role in understanding CRC biology and tailoring treatment strategies.Microsatellite instability (MSI-H) is a key feature in colorectal cancer (CRC) development, occurring in 15% of cases. It is characterized by mutations in microsatellite sequences due to defects in the mismatch repair (MMR) system, primarily involving MSH2, MLH1, and MSH6 proteins. MSI-H is associated with a better prognosis and can predict the effectiveness of chemotherapy in CRC. However, clinical trials have shown conflicting results regarding its predictive value for treatment response. MSI-H tumors are often located proximally in the colon, are poorly differentiated, and have a higher lymphocytic infiltration. They are less likely to metastasize and have a better prognosis compared to microsatellite stable (MSS) tumors. MSI-H tumors are resistant to 5-fluorouracil (5-FU) chemotherapy but more sensitive to irinotecan and oxaliplatin. Recent meta-analyses suggest that MSI-H patients have better survival rates, but there is inconsistency in the effectiveness of 5-FU-based chemotherapy. The future of CRC treatment lies in personalized therapy based on molecular characteristics, including MSI-H status. MSI-H is a significant prognostic and predictive factor in CRC, and its identification can guide treatment decisions. A prognostic model has been developed to predict MSI-H status based on clinical and pathological features, improving cost-effectiveness in diagnosis. Overall, MSI-H plays a crucial role in understanding CRC biology and tailoring treatment strategies.