Metastatic cancer can recur months or even years after apparently successful treatment of the primary tumor. While the exact mechanisms leading to cancer recurrence remain poorly understood, failure to completely eliminate dormant micrometastases and solitary metastatic cells is believed to be a major contributor. Thus, while not of initial clinical concern, metastatic dormancy is still a significant clinical problem. The emerging use of circulating tumor cells (CTCs) as prognostic and predictive biomarkers for monitoring and understanding metastatic disease may provide an opportunity to address this challenge. In this chapter we discuss the current knowledge relating to CTCs and tumor dormancy, and the relationship between the two with regard to metastasis biology and treatment. We also consider the clinical impact of monitoring for CTCs in the absence of symptomatic tumor recurrence and what is needed for such an approach to providing “actionable” information that will improve patient outcome.