The development and biological characteristics of tumor metastasis are influenced by multiple cell and host-associated factors. To study these factors experimentally, the necessity of choosing adequate in vivo model systems for human tumor metastasis is emphasized. Recent research has provided results that highlight the role of the microenvironment in determining important characteristics of the metastatic cells, including their degree of differentiation and sensitivity to drugs. Furthermore, evidence is presented as background for discussing the general validity of the notion of clonal selection of metastatic cells, and whether the metastatic phenotype is acquired through the last of a series of mutational events occurring during tumor progression.