Malignant transformation in humans occurs via different mechanisms including the activation of oncogenes and/or loss of tumor suppressor genes. Recently, DNA mismatch repair defects manifest as genome wide microsatellite instability have been described as an additional mechanism of tumorgenesis in humans. Tumors exhibiting widespread microsatellite instability as first described in studies of hereditary nonpolyposis colorectal cancer (HNPCC) are referred to as having a mutator or replication error (RER+) phenotype. Until recently, the occurrence of microsatellite instability has been primarily characterized in solid neoplasms. Several reports have now identified this mutator phenotype in a number of leukemias and lymphomas as well. This loss of DNA replication repair function may lead to increased mutations in genes critical to normal cell growth regulation and ultimately tumor initiation and/or progression.