For some time the epidemiologic evidence has suggested that the bulk of cancer in the population is related to the environment. And it’s interesting to see how research priorities within this category have shifted since Al and I arrived at NCI – from the pursuit of oncogenic viruses in the ‘60s, to chemical carcinogens in the ‘70s, to lifestyle factors in the ‘80s - all before the genomic and molecular evolution. While genetic and epigenetic factors clearly drive the development and progression of all cancer, the role of inherited genes has been difficult to assess. The burden of cancer due to high-penetrant gene mutations associated with the hereditary syndromes appears to be minor. But evidence is mounting that common, low-penetrant genes that have—may have a substantial impact through combinations with one another and with environmental factors, and it seems likely that gene-environment interactions hold the key to a large percentage of cancer. The so-called “spontaneous” category in the upper left refers to tumors that arise from random genetic events in the absence of known susceptibility or exposure. But the proportion of such cases, I think, will shrink as we achieve a better understanding of causal mechanisms.