WRN (Werner syndrome helicase) is a member of the RecQ DNA helicase subfamily. RecQ helicases are involved in multiple DNA processing steps including DNA replication, double-strand break repair, transcription and telomere maintenance and are therefore considered to serve as ‘genome caretakers’. Studies have shown that WRN helicase is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair. MSI is associated with a high mutational load and occurs in more than 20 tumours types and is frequent in colon, ovarian, endometrial and gastric cancers. Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. Thus, inhibiting the WRN helicase is an attractive strategy for the treatment of mismatch repair defective cancers.