It is well known clinically that advanced, bulky visceral metastatic disease is generally much less responsive to most anti-cancer therapies, compared to microscopic metastatic disease. This problem is exacerbated when treating cancers that have been previously exposed to multiple lines of therapy, and which have acquired a 'refractory' phenotype. However, mimicking such clinical treatment situations in preclinical mouse models involving the testing of new or existing cancer therapies is extremely rare. Treatment of 'metastasis', in retrospect, usually involves minimal residual disease and therapy naïve tumors. This could account in many instances for the failure to reproduce highly encouraging preclinical results in subsequent phase I or phase II clinical trials. To that end, we have embarked on an experimental program designed to develop models of advanced, visceral metastatic disease, in some cases involving tumors previously exposed to various therapies. The strategy first involves the orthotopic transplantation of a human cancer cell line, such as breast cancer cell line, into the mammary fat pads of immune deficient mice, followed by surgical resection of the resultant primary tumors that develops. Recovery of distant macroscopic metastases, usually in the lungs, is then undertaken, which can take up to 4 months to visibly form. Cell lines are established from such metastases and the process of orthotopic transplantation, surgical resection, and recovery of distant metastases is undertaken, at least one more time. Using such an approach highly metastatically aggressive variant sublines can be obtained, provided they are once again injected into an orthotopic site and the primary tumors removed by surgery. By waiting sufficient time after removal of the primary tumors, about only 1 month, mice with extensive metastatic disease in sites such as the lungs, liver, and lymph nodes can be obtained. An example of therapy being initiated in an advanced stage of such disease development is illustrated. Metastases that eventually stop responding to a particular therapy can be removed as a source of variant cell lines which have both 'refractory' and highly metastatic phenotypes. Such models may provide a more accurate picture of the potential responsiveness to an experimental therapy so that a high degree of responsiveness observed could be a factor in deciding whether to move a particular therapy forward into phase I/phase II clinical trial evaluation. An example of this is illustrated using doublet metronomic low-dose chemotherapy for the treatment of advanced metastatic breast cancer, using two conventional chemotherapy drugs, namely, cyclophosphamide and UFT, a 5-FU oral prodrug.