Once metastatic cells successfully seed at distant sites, their clinical detection and danger to the host are dependent on growth to form gross metastases. Metastatic tumor cells proliferate in response to local paracrine growth factors and inhibitors, and their growth also depends on production and responses to autocrine growth factors. A major organ-derived (paracrine) growth factor from lung tissue-conditioned medium has been isolated that differentially stimulates the growth of cells metastatic to brain or lung. Characterization of this mitogen demonstrated that it is a transferrin or a transferrin-like glycoprotein. Furthermore, antibodies to transferrin can remove significant growth activity from lung tissue-conditioned medium. Cells that are metastatic to brain or lung express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to liver. Growth responses of metastatic cells and organ preferences of colonization appear to change during progression to more malignant states. At early stages of metastatic progression there is a tendency for many common malignancies to metastasize and grow preferentially at particular sites, suggesting that paracrine growth mechanisms may dominate the growth signals at this stage of progression. In contrast, at later stages of metastatic progression widespread dissemination to various tissues and organs occurs, and autocrine growth mechanisms may dominate the growth responses of metastatic cells. Ultimately, the progression of malignant cells to completely autonomous (acrine) states can occur, and at this stage of metastatic progression cell growth may be completely independent of autocrine and paracrine growth factors or inhibitors.