Mismatch repair (MMR) defects and microsatellite instability (MSI) are two genetic alterations that have been documented in a wide variety of human cancers, including some that involve the skin. Available evidence indicates that these two features are sometimes directly related, although their connection seems to be indirect or nonexistent in other instances. The purposes of this review are to summarize the variable relations between MMR and MSI as deduced from analysis of a diverse array of human neoplasms and to give brief insights as to the other molecular mechanisms potentially involved in the maintenance of genomic stability.