The cure rate for the majority of cancer patients is >90 % if the diagnosed tumor has not spread beyond the tissue of origin. However, when tumor cells have established colonies elsewhere, the cancer is often incurable. Neoplasms have been diagnosed for approximately four millennia and even the earliest medical practitioners recognized that the most lethal attribute of neoplastic cells is their ability to disseminate and colonize secondary sites. Despite these well-recognized facts, the majority of cancer research funding still focuses on primary tumorigenesis. Relatively few funded grants from the NIH include the word metastasis and significantly fewer actually perform metastasis research. In recognition of the need to study metastasis, a major push has been toward the last frontier of cancer research. This chapter provides a brief overview of what is known regarding the cellular and molecular events of a primary tumor mass progressing to form a distinct secondary macroscopic lesion.