ESTROGENS have been implicated as causative agents in tumor development for more than half a century. A number of mammalian species, including primates as well as man, are susceptible to the formation of neoplasms, both benign and malignant, at various organ sites after chronic exposure to sex hormones (1). In an effort to gain an understanding of how these hormonal induced neoplastic changes take place, the estrogeninduced tumors in the hamster kidney and liver have become the most intensively studied experimental systems in hormonal carcinogenesis (2–8). Based mainly on our studies over the years, we had proposed that estrogens effect neoplastic transformation in the hamster kidney and liver via their hormonal and metabolic activities operating in concert (9, 10). Metabolic activity of estrogens is presently defined as the generation of reactive metabolites, directly or indirectly, and their subsequentbinding to cellular macromolecules. Different laboratories have proposed the primacy of one or the other of these activities in an effort to explain how estrogens elicit tumorigenesis in the hamster. Given the present state of knowledge, it is deemed appropriate at this time to critically review these considerations individually to determine their contributions, if any, to estrogen-induced tumorigenesis in the hamster kidney and liver. A central concept in our review is that conclusions based on results obtained from either biochemical or in vitro data must reasonably correlate with findings in the whole animal to be significant, unless there is a compelling rationale presented to explain the discrepancy. Hormonal activity in this context is defined as receptor-mediated cell proliferation as well as the induced syntheses of specific macromolecules and membrane effects of hormones in target tissues.