Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will distinguish accurately those histologic lesions and disseminated cells with a high probability of causing clinically important metastatic disease from those that will remain indolent. While the development of new diagnostic markers of metastasis was the initial motivation for many studies, the biologic approach used to identify metastasis-suppressor genes has provided surprising insights into the in vivo mechanisms regulating the formation of metastases. This review and perspective describes the evolving view of the mechanisms that regulate metastasis and the importance of metastasis-suppressor genes in this process. The known metastasis-suppressor proteins or genes and the microcell-mediated chromosomal transfer strategy used to identify many of them are reviewed. New evidence for the role of these metastasis-suppressor proteins or genes in regulating the growth of disseminated cancer cells at the secondary site, the potential for the identification of novel therapeutic targets, and the multidisciplinary approach needed to translate this information into clinical tools for the treatment of metastatic disease are discussed.