The major cause of death from cancer is metastases that are resistant to conventional therapies. Several reasons account for treatment failure in patients with metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects a small subpopulation of cells that preexist within a parental neoplasm. Although metastases can have a clonal origin, genetic instability results in rapid biological diversification and the regeneration of heterogeneous subpopulations of cells. Third, and perhaps the most important principle for the design of new cancer therapies, is that the outcome of metastasis depends on multiple interactions (“cross-talk”) of metastatic cells with homeostatic mechanisms which the tumor cells usurp. The organ microenvironment can influence the biology of cancer growth, angiogenesis, and metastasis in several different ways. For example, the survival and growth of tumor cells are dependent on angiogenesis, which is mediated by an imbalance between positive and negative regulating molecules released by tumor cells, normal cells surrounding a tumor, and infiltrating lymphoid cells. Many cytokines that stimulate or inhibit angiogenesis are present in different tissues, and thus the organ environment profoundly influences this process. Moreover, the organ microenvironment can also influence the response of metastases to chemotherapy by regulating the expression of different drug resistance genes, such as mdr-1. The finding that the resistance of metastases to some chemotherapeutic agents can be mediated by epigenetic mechanisms has obvious implications for therapy. The identification of organ-specific cytokines that can upregulate expression of mdr-1 (or other resistant mechanisms) may suggest an approach to overcome the resistance of some metastases to particular chemotherapeutic agents. Therefore therapy of metastasis should be targeted not only against metastatic tumor cells, but also the homeostatic factors that are favorable to metastasis, growth, and survival of the metastatic cells.