Immunotherapy has reshaped therapeutic strategies for many solid tumors in recent years. However, only a small subset of colorectal cancer (CRC) patients responds to immunotherapy-based treatment. Clinical trials have demonstrated robust antitumor activity of immunotherapy with immune checkpoint inhibitors (ICI) in previously treated, and treatment-naive patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) advanced CRC. Currently, pembrolizumab, an ICI that works by blocking programmed death 1 (PD 1) receptor on T lymphocytes, is approved in the first-line setting for dMMR/MSI-H advanced CRC patients based on phase III, randomized KEYNOTE-177 trial data demonstrating the superiority of pembrolizumab over chemotherapy. Approximately 10–18% of early-stage and 5% of advanced CRC patients harbor the dMMR/MSI-H signature, limiting the utility of immunotherapy in the treatment of CRC. The vast majority of CRCs harbor proficient mismatch repair (pMMR) tumors that are immunologically inert. The studies with immunotherapy in pMMR CRC have demonstrated disappointing results thus far. A variety of combination strategies are currently being investigated to enhance the immunogenicity of the proficient MMR (pMMR) CRC to expand the role of immunotherapy in this patient group. Impressive antitumor activity of ICIs in patients with advanced dMMR/MSI-H CRC has led to trials with ICIs in patients with early-stage CRC harboring dMMR/MSI-H signature, both in the neoadjuvant and adjuvant settings, with promising preliminary results. Studies exploring potential biomarkers to predict immunotherapy response are another area of active investigation.