PURPOSE: Tumor cell genotype and phenotype have been considered the only determinants supporting cancer growth and metastasis. This review focuses on the published literature that suggests that tumor-microenvironment interaction has a decisive role in controlling local cancer growth, invasion and distant metastasis. As this review shows, genetic alterations in prostate cancer cells alone are not enough to confer metastatic status without a supporting tumor microenvironment. Effective therapeutic targeting requires a deeper understanding of the interplay between tumor and stroma. Approaches co-targeting tumor and stroma already show promise over the conventional targeting of tumor cells alone in preventing prostate cancer progression and eradicating preexisting or newly developed prostate cancers in bone and visceral organs. MATERIALS AND METHODS: A literature survey using the MEDLINE database was performed in basic and clinical publications relevant to tumor-host microenvironment interaction. Information pertinent to the biology and therapy of prostate cancer local growth and distant metastases was specifically emphasized. RESULTS: Tumor associated stroma actively fuel the progression of prostate cancer from localized growth to the invasion of surrounding tissues, and the development of distant bone and visceral organ metastasis. In concert with this progression tumor cells recovered from metastatic sites could represent a subpopulation of preexisting tumor cells or could be a newly acquired variant subsequent to tumor-stromal interaction. Experimental data from our laboratory and others suggest that permanent genetic and phenotypic changes occur in prostate cancer cells after 3-dimensional co-culture in vitro or when co-inoculated and grown with inductive stromal cells in vivo. These results support the idea that newly acquired variants are the dominant mechanism of prostate cancer progression. Intercellular communication between prostate cancer cells and organ specific stroma, including prostate and marrow stroma, could involve diffusible soluble and solid matrix molecules as mediators, leading to the development of metastasis. This presents a new opportunity for therapeutic targeting for the treatment of benign and malignant growth of the prostate glands. This review summarizes specific research implicating tumor-microenvironment interaction as the molecular basis of cancer progression, providing a rationale for targeting tumor and the tumor associated microenvironment in the management of androgen independent and bone metastatic prostate cancer progression in patients. CONCLUSIONS: Cancer is not a single cell disease. Aberrant cancer cells and their interactive microenvironment are needed for prostate cancer to progress to androgen independence and distant metastasis. It is highly plausible that newly evolved prostate cancer cell clones dominate cancer metastasis after cell-cell and cell-matrix interaction with the host microenvironment, rather than the selection or expansion of a preexisting prostate cancer cell clone(s). Based on this premise potential molecular targets in the microenvironment are especially emphasized. Further elucidation of the molecular mechanisms underlying tumor-stromal interaction may yield improved medical treatments for prostate cancer growth and metastasis.