Microsatellite instability (MSI) is a key feature of cancers with defective DNA mismatch repair, including colorectal, gastric, endometrial, and ovarian cancers. Tumors with MSI depend on the Werner syndrome protein (WRN) for genomic stability, making WRN an attractive therapeutic target. WRN inhibitors exploit the concept of synthetic lethality, inducing selective DNA damage and cell death in MSI tumors while sparing microsatellite stability (MSS) tumor cells or normal cells. Preclinical studies have shown that the efficacy of WRN inhibitors is enhanced when combined with DNA damage response inhibitors or immunotherapy. This review delineates the molecular mechanisms underlying WRN dependency in MSI cancers and explores the therapeutic potential of WRN inhibition. WRN inhibitors represent a promising strategy in precision oncology, especially for MSI tumors, and have the potential to enhance patient outcomes, either as monotherapy or in combination with other treatments.