Genetic epidemiology studies in hereditary non-polyposis colorectal cancer (HNPCC) have the potential to radically improve assessment of disease risk such that more individualised information can be provided to patients susceptible to developing disease. Studies of HNPCC initially focused on disease associations and the definition of the disease and its association with different cancers within the context of an inherited predisposition. With the identification of the genetic basis of HNPCC, new insights into the disease have been forthcoming and many advances in our understanding have been made. There have been many reports examining potential modifier genes in HNPCC, yet the results remain controversial as many findings have not been replicated and therefore no clear consensus as to the role of specific modifier genes has been reached. This review focuses on some of the factors associated with disease risk in HNPCC and where some of the difficulties lie in assessing the value of genetic epidemiology studies in this disorder.