Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will accurately distinguish those histologic lesions and disseminated cells that have a high probability of causing clinically important metastatic disease from those cells that will remain indolent. Despite the explosion in new information regarding the genetics of cancer, only six human genes have thus far been shown to functionally suppress metastasis. The present review and perspective describes the evolving view of the mechanisms that regulate metastasis, and the importance of metastasis-suppressor genes in this process. Specifically, the clinical problem of metastatic prostate cancer, the identification of metastatic colonization as a therapeutic target, and the identification and functional characterization of prostate cancer metastasis-suppressor genes are discussed.