A new mechanism leading to cancer has been delineated in the last two years when genes whose mutations cause susceptibility to hereditary nonpolyposis colorectal cancer, HNPCC, have been mapped, cloned, and characterized. The genes involved belong to a family of DNA mismatch repair genes, and the homozygous effects of their mutations lead to a so-called mutator or replication error phenotype characterized by genome-wide mutations most readily detectable as lengthening or shortening of microsatellite repeats in tumor tissue as compared to normal tissue from the same individual. Germline mutations are inherited in a dominant Mendelian fashion causing the multiorgan cancer susceptibility syndrome misnamed HNPCC. Clinically, the molecular characterization of these mutations in affected individuals now allows genotype-phenotype correlations, and a new view of the natural history of the disease may arise. In at risk individuals, it allows predictive testing for cancer susceptibility, enhanced clinical surveillance with the aim of early cancer detection and cure, and preventive measures.