Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials. This correlation has been first reported in colorectal cancers, but similar results have been observed also in other cancer types. The possible mechanism behind this correlation may be the higher mutational load observed in mismatch repair deficient tumors, leading to neoantigens formation, recruitment of immune cells, and release of proinflammatory factors in the microenvironment. These results support an approach to treatment based on assessment of the genomic stability of the tumor besides its biologic characteristics and may change our therapeutic decision making process. However, due to the small percentage of patients with tumors displaying mismatch repair deficiency, data from clinical trials should not be considered definitive and need further confirmation.