Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the early occurrence of colorectal cancer--usually located in the right colon--frequent synchronous and metachronous colorectal malignancies, and association with tumors of other organs (especially endometrium, skin and stomach). In typical cases the diagnosis may be easy, but in many other instances small size of families, possible low penetrance and frequency of phenocopies may render the identification of these families extremely more complex. To provide a basis of uniformity in assessing HNPCC families, well-defined clinical guidelines have recently been proposed (the "Amsterdam Criteria"). Various studies, in different countries, indicate that the frequency of HNPCC is in the order of 3 to 5% of all colorectal tumors; at variance with these observations, much lower rates have recently been detected in Northern Ireland. The reasons of these differences are unclear. Segregation analysis repeatedly showed that the autosomal dominant inheritance was the most plausible model in order to explain cancer aggregation and verticality in HNPCC families; in accordance with this view, recessive and polygenic models were usually rejected. In addition, various anecdotal reports support the Mendelian nature of HNPCC. In conclusion, the identification of HNPCC remains a difficult task in many cases; moreover, it is likely that in analogy with adenomatosis coli 'single cases' (i.e., first mutation) might be frequent, and at present we can only suspect the disease in a single individual. It is likely, however, that the recent and exciting results of molecular biology will give in a few years of substantial contribution in the management of these patients.