After entry into the blood, cells from disseminating malignant tumors are rapidly distributed to many organs, but they only grow to form metastases in certain sites. Clinical and pathologic observations on tumor metastasis in humans and in animals have confirmed that the distribution of these secondary neoplasms is related to the site and type of the primary neoplasm. Numerous studies now indicate that success or failure in producing metastatic deposits is influenced by interaction between the tumor cells and the microenvironment of the organ in which they lodge. In the present investigation, the mechanisms by which the microenvironmental conditions of specific organs may influence tumor cell survival and behavior and hence metastasis distribution were investigated in vitro with the use of spontaneous mouse mammary carcinomas from C3H/Avy mice. Some organs (lung, ovary) promoted the survival and the attachment of the tumor cells to the substratum, while others (liver, thyroid gland) consistently diminished survival of the tumor cells in the flask. These effects were shown to be due to soluble substances diffusing out of the organs, the dose dependency of which was demonstrated. It is known that in vivo murine mammary tumors develop metastases mainly in the lungs and occasionally in the kidneys or ovaries (if inoculated via the aorta). The effects of these same organs on tumor cells in vitro were thus in good agreement with the in vivo observations. The findings are compatible with the hypothesis that normal organs can usually suppress the formation of tumor metastases and that tumors that succeed in establishing metastases have evolved means of escaping the inhibitory effects of organs in which the deposits are found.