Background: Although the prognostic value of CTC enumeration in metastatic breast cancer (MBC) is well understood, the value of taking into account the molecular characteristics of CTCs in treatment decision requires further investigation. Trial Design: The DETECT studies are prospective, multicenter, open-label clinical trials designed for patients with HER2-negative MBC and CTCs in the peripheral blood. DETECT III is a two-arm, phase III study for patients with HER2-positive CTCs, randomized to physician’s choice chemotherapy with or without additional HER2-targeted treatment with lapatinib. DETECT IV is a single-arm phase-II study including postmenopausal women with hormone-receptor-positive, HER2-negative MBC and HER2-negative CTCs that will be treated with the mTOR-inhibitor everolimus in combination with an endocrine therapy of physician’s choice. Specific aims: The primary objective of both trials is to estimate the clinical efficacy of treatments, assessed by the CTC clearance rate for DETECT III and progression-free survival (PFS) for DETECT IV. Present and target accrual: Overall, about 2000 MBC patients with a HER2-negative primary tumor will have to be screened to be able to include 120 patients with HER2-positive CTCs for DETECT III (started in February 2012) and 400 patients with HER2-negative CTCs for DETECT IV (started in December 2013). So far, 751 patients have been screened for CTCs. Methods: Prevalence of CTCs at various time points as well as the HER2 status of CTCs will be determined using the FDA-approved CellSearch System (Veridex, USA). Survival endpoints will be estimated using the Kaplan-Meier method. Perspectives: The DETECT III trial is the first study in which treatment is based on phenotypic characteristics of CTCs. If this trial succeeds in proving efficacy of lapatinib in patients with HER2-negative primary tumor but HER2-positive CTCs, it may lead to new treatment strategies for MBC. DETECT IV complements DETECT III with regard to additional therapy indications. The innovative study concept of these clinical trials with therapy decisions being based on prevalence and molecular phenotypes of CTCs is an important step towards a more personalized cancer treatment for MBC. Clinical trial information: NCT02035813.