The metastatic process remains one of the most enigmatic aspects of cancer pathogenesis. The concept of "cancer stem cells" (CSC) has evolved over the past decade, elucidating the presence of a distinct population of cells which is defined by their high tumorigenic capacity and long-term self-renewal ability. In this editorial, we discuss the association between cancer stem cells and circulating tumor cells (CTC) (see article by Grinshpun et al. in this issue) and the role of CSC in mediating the formation of cancer metastases. Intensive research is ongoing on the clinical significance of CTC in a wide variety of malignancies; CTC are a heterogeneous population of cells which include CSC as well, a major player in the formation of metastases. A better understanding of the unique properties of CSC and their interaction with the microenvironment will enable the development of ways to detect and target this cell population.