The process of metastasis consists of a series of linked, sequential steps. Although some of the steps in this process contain stochastic elements, metastasis as a whole favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with various host factors. Organ-specific metastases have been demonstrated in a variety of tumors and may even be specific to a particular site within one organ. Studies from our laboratory and from others have shown that the implantation of human cancer cells derived from surgical specimens into correct anatomic sites of nude mice provides a suitable model of metastasis of human tumors. Clonal analysis of human melanomas revealed that these tumors are heterogeneous for metastatic properties and that growth in the environment of specific organs is selective. These data suggest that systemic physiologic signals can be recognized by neoplastic cells, presumably by mechanisms similar to those shared by their normal cell counterparts. Elucidation of the mechanisms that regulate metastasis should lead to better therapeutic interventions.