Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively treat it is still emerging. Metastasis requires the acquisition of a succession of traits to disseminate, variably enter and exit dormancy, and colonize distant organs. The success of these events is driven by clonal selection, the potential of metastatic cells to dynamically transition into distinct states, and their ability to co-opt the immune environment. Here, we review the main principles of metastasis and highlight emerging opportunities to develop more effective therapies for metastatic cancer. Metastasis is the most lethal manifestation of cancer, but our understanding of its biology and how to effectively treat it is rapidly advancing. This review highlights established and emerging principles of metastasis and provides a framework to develop more effective therapies for metastatic cancer.