Metastasis is powered by disseminated cancer cells that re-create a full-fledged tumor in unwelcoming tissues, away from the primary site. How cancer cells moving from a tumor into the circulation manage to infiltrate distant organs and initiate metastatic growth is of interest to cancer biologists and clinical oncologists alike. Recent findings have started to define the sources, phenotypic properties, hosting niches, and signaling pathways that support the survival, self-renewal, dormancy, and reactivation of cancer cells that initiate metastasis: metastatic stem cells. By dissecting the biology of this process, vulnerabilities are being exposed that could be exploited to prevent metastasis.