The article reviews the clinical development and rationale for using immunotherapy in colorectal cancer (CRC), focusing on the subset of patients with mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H) tumors. Two PD1-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in these patients, leading to FDA approval. The review highlights the long-term durable remission achieved by immunotherapy in a subset of patients, particularly those with dMMR-MSI-H metastatic CRC. It discusses the clinical trials that led to regulatory approvals and the mechanisms by which immune checkpoint inhibitors (ICIs) work. The article also explores the challenges and future directions in expanding the efficacy of immunotherapy to early-stage CRC and mismatch-repair-proficient, microsatellite-stable (pMMR-MSI-L) CRC. Additionally, it covers emerging approaches to target the immune microenvironment, such as bispecific antibodies, combination therapies with chemotherapy and antiangiogenic agents, and the potential of precision prevention for individuals with Lynch syndrome. The review emphasizes the need for further research to identify predictive biomarkers and develop strategies for treating pMMR-MSI-L CRC.The article reviews the clinical development and rationale for using immunotherapy in colorectal cancer (CRC), focusing on the subset of patients with mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H) tumors. Two PD1-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in these patients, leading to FDA approval. The review highlights the long-term durable remission achieved by immunotherapy in a subset of patients, particularly those with dMMR-MSI-H metastatic CRC. It discusses the clinical trials that led to regulatory approvals and the mechanisms by which immune checkpoint inhibitors (ICIs) work. The article also explores the challenges and future directions in expanding the efficacy of immunotherapy to early-stage CRC and mismatch-repair-proficient, microsatellite-stable (pMMR-MSI-L) CRC. Additionally, it covers emerging approaches to target the immune microenvironment, such as bispecific antibodies, combination therapies with chemotherapy and antiangiogenic agents, and the potential of precision prevention for individuals with Lynch syndrome. The review emphasizes the need for further research to identify predictive biomarkers and develop strategies for treating pMMR-MSI-L CRC.