With active screening for early detection and advancements in treatment, there has been a significant decrease in mortality from breast cancer. However, a significant proportion of patients with non-metastatic breast cancer at time of diagnosis will relapse. Therefore, it is suggested that the dissemination of bloodstream tumor cells (circulating tumor cells, CTCs) undetectable by currently available diagnostic tools occurs during the early stages of breast cancer progression, and may be the potential source of micrometastases responsible for treatment failures. Here, we review the clinical significance of CTCs, as detected by the FDA-approved CellSearch® System, in both metastatic and non-metastatic breast cancer patients. Studies so far suggest that CTCs are prognostic of poorer outcomes in breast cancer patients; however, there is currently insufficient data to support use of CTC data to guide treatment. Therefore, there are ongoing studies to evaluate the utility of assessing CTC phenotypes to develop personalized breast cancer treatment, which will be reviewed in this chapter.