Human neoplasms are biologically heterogeneous. The extensive cellular diversity found in malignant neoplasms is generated by the rapid emergence of clonal subpopulations of tumor cells with different properties that include invasion, metastasis and responsiveness to treatment. Studies in rodent systems have indicated that cancer metastases can be clonal in their origin and that different metastases can originate from different progenitor cells from the primary tumor. This metastatic heterogeneity of tumor cells has many ramifications for studies of tumor biology, in general, and studies of therapy, in particular. The heterogeneous nature of metastatic human neoplasms can now be studied under defined conditions in healthy athymic nude mice. The neoplasms must be free of mouse pathogens and the mice must be kept in specific-pathogen-free conditions. Careful consideration must be given to the intimate tumor-host relationship for each tumor system studied, because the metastatic potential of human neoplasms can vary with the site of implantation into nude mice. Several methods for studying the biology of human neoplasms in the nude mouse are described as well as techniques to assure the success of these studies. The data show that the healthy young nude mouse can be a useful in vivo model for ascertaining the metastatic potential of human neoplasms, for selecting and maintaining cell variants of high metastatic potential from heterogeneous human tumors, and for studying therapeutic agents directed against metastatic cells proliferating in visceral organs.