Circulating tumor cells (CTCs), enumerated by the Food and Drugs Administration-cleared CellSearch® system, are an independent prognostic factor of progression-free survival (PFS) and overall survival (OS) in metastatic breast cancer (MBC) patients. Several published papers demonstrated the poor prognosis for MBC patients who presented basal CTC count ≥5 in 7.5 mL of blood. Therefore, the enumeration of CTCs during treatment for MBC provides a tool with the ability to predict progression of disease earlier than standard timing of anatomical assessment using conventional radiological tests. Randomized clinical trials are ongoing to demonstrate whether CTCs detected by CellSearch® may help to guide treatments in MBC patients and improve prognosis. Moreover, the ability to perform molecular characterization of CTCs might identify a new druggable target in MBC patients. For example, the RT-PCR-based approach AdnaTest BreastCancerSelect™ showed a high discordance rate in receptor expression between the primary tumors and CTCs. Theoretically, the phenotypic analysis of CTCs can represent a "liquid" biopsy of breast tumor that is able to identify a new potential target against the metastatic disease.