Cancer risk for people with an inherited mutation in a DNA mismatch repair gene (Lynch syndrome) depends on the gene that is mutated; a fact that challenges current screening guidelines that recommend the same screening and prevention strategies for all carriers of all mismatch repair genes. A further complication is that it is becoming increasingly apparent, even within carriers of mutations of a specific gene, that cancer risk is heterogenous. By studying cancer diagnoses in thousands of families with Lynch syndrome (from the International Mismatch Repair Consortium), we have been able to estimate how much these cancer risks vary from one family to another. For example. while some people with a DNA mismatch repair gene are almost certain to develop colorectal cancer, are substantial proportion are at low risk; i.e. the often-quoted estimates of risk are not applicable to most mutation carriers. This risk heterogeneity is consistent with existence of strong genetic and environmental cancer risk factors that aggregate in families. If these could be reliably identified, the risk reduction for Lynch syndrome could be tailored to personal risk.