Colorectal cancer (CRC) rates for Japanese migrants to the United States increased rapidly to surpass the level of the host population. CRC rates for the Japanese in Hawaii and California are now the highest in the world. Rates for this disease have also increased in Japan, presumably as the result of the westernization of the diet. A series of population-based studies in Hawaii was undertaken to determine which dietary factors are responsible for this remarkable susceptibility of the Japanese to CRC and whether genetic factors are also involved. A first case-control study suggested that a high intake of red meat is a major risk factor for the disease in Hawaii Japanese men and that family history of CRC among first-degree relatives may strongly modify this association. A case-control family study is currently being completed to explore further the interaction between family history and the intake of red meat after adjustment for environmental covariates among family members. Also, a segregation analysis will guide gene discovery studies among high-risk Japanese families being recruited in the Cooperative Family Registry for Colorectal Cancer Studies. Retrospective and prospective studies are also ongoing to test associations of CRC with specific polymorphisms in genes controlling the metabolic activation or detoxification of the carcinogens associated with a diet high in red meat. Preliminary results suggest an association of the combined rapid NAT2 genotype and rapid CYP1A2 phenotype with CRC in individuals consuming well-done red meat. Populations in which dramatic changes in cancer incidence have occurred may offer opportunities to identify gene-environment interactions.