The nutritional intake of phytoestrogens seems to reduce the risk of breast cancer or other neoplastic diseases. However, these epidemiologic findings are controversial because low phytoestrogen doses, achievable through soy-rich diets, stimulate the proliferation of estrogen-sensitive tumor cells. The question of whether such phytochemicals prevent cancer, or pose additional health hazards, led us to monitorglobal gene expression changes induced by phytoestrogens (daidzein, coumestrol, enterolactone, resveratrol) or a typical soy product (soymilk), from which the phytochemicals were extracted by reverse/normal phase chromatography. In each case, phytoestrogens were used to treat human cells representing a common model system for mammary tumorigenesis. Analysis of messenger RNA on highdensity microarrays revealed that soy phytoestrogens induce a genomic fingerprint that is indistinguishable from the transcriptional effects of the physiologic hormone 17β-estradiol. Highly congruent responses were also observed by comparing the physiologic estradiol with phytoestrogen standards. More diverging transcriptional profiles were generated when an inducible promoter was used to reconstitute the expression of estrogen receptor β. We conclude that phytoestrogens mitigate estrogenic signaling in the presence of both estrogen receptor subtypes but, in late-stage cancer cells lacking estrogen receptor β, these phytochemicals may contribute to a tumor-promoting transcriptional signature.