Liquid biopsy using blood components to assess circulating tumor DNA (ctDNA) is rapidly becoming a new standard-of-care technology in many tumor types, including breast cancer, due to the potential to provide predictive and prognostic information. The minimally invasive and repeatable nature of plasma based mutational testing is appealing for patients and facilitates enhanced disease monitoring. It is important for the clinician to understand the benefits and limitations of this emerging assay and the potential applications in breast cancer. Multiple technologies have been employed to assess breast cancer ctDNA with high sensitivity and specificity leading to assays that have been useful in research trials and are entering widespread clinical application. ctDNA analysis of breast cancer is of clinical utility today in selecting targeted therapy for advanced breast cancer, most notably by assessing PIK3CA mutations in hormone receptor–positive, HER2-negative disease. It will be employed in the near future in a variety of clinical settings including early detection of primary breast cancer, minimal residual disease after initial therapy, and use in advanced breast cancer for prognosis, early identification of non-response, and monitoring genomic markers of resistance.