Background: Circulating tumor cells (CTCs) are found in blood samples of patients with early as well as metastatic breast cancer (MBC). The prognostic and predictive value of CTCs, whose phenotype may differ from the primary tumor, has been described already. However, treatment decisions often still result from the primary tumor’s phenotype without considering CTC-characteristics. The importance of CTC phenotypes for guiding therapeutic decisions will be investigated within the DETECT studies. Methods: The DETECT study concept provides a prospective, multicenter, open-label clinical trial program comprising two phase III studies (DETECT III and V) and one phase II study (DETECT IV). Women with HER2-negative MBC are tested for CTCs and their HER2-phenotype. CTC detection is performed by the FDA-approved CellSearch System (Janssen Diagnostics, Raritan, USA). Patients with HER2-positive CTCs are recruited into DETECT III and randomized to a physician’s choice chemo- or endocrine therapy +/- additional HER2-targeted treatment with lapatinib. Patients with only HER2-negative CTCs are included in DETECT IV. Postmenopausal women with hormone-receptor (HR)-positive MBC are treated with everolimus and a physician’s choice endocrine therapy (DETECT IVa); women with triple-negative MBC or HR-positive tumors with indication for chemotherapy receive eribulin (DETECT IVb). In DETECT V/CHEVENDO, which started in autumn 2015, women with HER2- and HR-positive MBC are randomized to a dual HER2-directed therapy with pertuzumab and trastuzumab plus either chemotherapy or endocrine therapy. CTC-presence is not obligatory in DETECT V, but translational research projects focus on CTC-enumeration and the assessment of marker expression on CTCs in order to calculate an endocrine-responsiveness-score, which will be evaluated regarding to its suitability to predict treatment success. Perspective: Changes in the dynamic of CTCs during therapy and their HER2-phenotype may influence following therapy decisions. The DETECT study program evaluates the prognostic and predictive role of CTCs as well as a CTC based therapy and enables the establishment of a more personalized therapy for patients with MBC. Clinical trial information: NCT01619111, NCT 02035813, NCT02344472