Over the past few decades, substantial progress has been made in the diagnosis and treatment of breast cancer. Early identification of relapsed and metastatic disease has been a primary focus of ongoing research. Circulating tumor cells (CTCs) are implicated as harbingers of metastases. With advances in detection technologies, CTCs offer the option for real-time liquid biopsies. Methods to identify CTCs in the bloodstream by physical or biochemical properties, although feasible, still require improvements to promote widespread, reproducible use. Sufficient data support enumeration and assessment of changes in the number of CTCs as prognostic indicators, but controversy around their predictive utility for selecting treatments remains. As the technology to detect CTCs and characterize their heterogeneous molecular profile evolves, additional information will likely be obtained to guide targeted and individualized therapies.