Blood analytes as liquid biopsies, mirror intra-tumoral heterogeneity and give insights about clonal evolution for improved therapeutic decisions and for personalized treatment. Moreover, serial sampling is enabled by the minimal invasive nature of blood draw and cell-free DNA (cfDNA), circulating tumor cells (CTCs) and extracellular vesicles (EVs) may be sensitive enough to detect disease progression earlier than contemporary visual staging methods. To gain comprehensive insights into the genomic and transcriptomic complexity in metastatic breast cancer (MBC) useful for therapy management, we aimed to isolate and analyze mRNA and gDNA from circulating tumor cells (CTCs), mRNA from extracellular vesicles (EVs) and cell-free DNA (cfDNA) from an “all from one tube” format. This project aimed to elucidate the interdependence of different liquid biopsy analytes and the value of a multi-parametric approach in clinical practise. Direct comparison of matched circulating tumor cell (CTC) mRNA and extracellular vesicle (EV) mRNA, as well as comparison of matched CTC genomic DNA (gDNA) and cell-free DNA (cfDNA) in blood from metastatic breast cancer patients drawn at the progressive time point revealed the additive value of all tested liquid biopsy analytes. Each analyte showed synergistic potential for therapy management, thus, the comprehensive picture of the genomic and transcriptomic complexity depicted by a multimodal liquid biopsy approach might enhance the identification of actionable targets for individual therapy strategies in each individual MBC patient in the future.