Appropriate management of familial colorectal cancer revolves around the diagnosis of the underlying genetic syndrome. This necessitates an interdisciplinary approach allowing integration of clinical, morphological, and molecular evidence that may involve several members of the same family. Genetic disorders express themselves over time, whereas clinical investigation of family members is likely to be episodic. Generic features of hereditary colorectal cancer syndromes include a positive family history, early age at onset, multiple neoplasms, and extracolonic lesions of either a developmental or neoplastic nature. Deriving a complete description of a genetic disorder is hampered by the need to trace and obtain tissue samples from many institutions. This review examines the usefulness of tissue-based investigations, both morphological and molecular, in raising the suspicion of familial colorectal cancer, providing a definitive tissue diagnosis and contributing to the larger body of diagnostic evidence. The account focuses on the two most well-studied syndromes--familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC)--but consideration is also given to less well-understood syndromes. Some of these, notably hyperplastic polyposis and mixed polyposis, may closely mimic FAP or HNPCC.