With the recent U.S. Food and Drug Administration approvals of pembrolizumab and nivolumab for refractory deficient mismatch repair metastatic colorectal cancer, immune checkpoint inhibitors have now entered into clinical care for gastrointestinal cancers. Extensive ongoing efforts are exploring additional combinations of therapy in both deficient and proficient mismatch repair colorectal cancer. This review will outline the current status of such efforts and discuss the critical aspects of recognition and management of immune-related toxicities from checkpoint inhibitors.