A study of variation in cancer incidence among the Navajo Indians, given their relative racial and environmental homogeneity, could provide important clues to etiology and, ultimately, to cancer control. A family with Lynch syndrome II, which was originally described in a Navajo kindred, has received follow-up eight years later. Three at-risk relatives have had newly diagnosed colorectal cancer. These findings were highly predictable, given knowledge of the natural history and genetics of this autosomal dominantly inherited disorder. This disorder is believed to be the first example of hereditary colorectal cancer of any type among American Indians. Given the ubiquitous nature of hereditary colorectal cancer disorders, it is likely that other, similar, colorectal cancer-prone families exist among the Navajo. Biomolecular technology employing DNA analysis, when it becomes available, should aid in cancer genetic diagnosis. Meanwhile, knowledge of hereditary colon cancer’s natural history, coupled with painstaking compilation of the pedigree, will be mandated for hereditary colorectal cancer syndrome diagnosis.