Background In metastatic breast cancer, blood-based diagnostics have become a major focus of oncological research in the last two decades. Detection of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) has the potential to improve prognosis assessment and complement standard therapy monitoring tools. Summary To date, several large analyses have confirmed high CTC counts as an independent prognostic factor. Persistently high CTC numbers during systemic treatment are associated with early progression but it remains to be clarified which therapeutic options should be offered to such patients since the SWOG 0500 trial failed to show benefit from early switch to another chemotherapy regimen in patients with CTC persistence. In comparison, evidence on the prognostic value of ctDNA is still limited. Most importantly, liquid biopsy-guided treatment interventions have been investigated in several trials. In patients with hormone receptor positive HER2 negative metastatic breast cancer CTC-driven therapy choices resulted in similar PFS to physician’s choice treatment. Recently, the DETECT III trial has shown that patients with HER2 negative metastatic breast cancer and HER2 positive CTCs may benefit from targeted anti-HER2 treatment with lapatinib. ctDNA-driven therapy selection has already been approved in clinical routine: alpelisib is the first targeted treatment indicated on the basis of a ctDNA test. Key messages CTCs and ctDNA predict clinical outcome and have a potential to improve therapy choices in metastatic breast cancer.