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Clinicians have limited ability to monitor patients with breast cancer (BC) for signs of drug resistance. In the metastatic setting, early detection of treatment resistance is paramount. Development of minimally invasive blood-based assays, with a focus on circulating tumour cells (CTCs) and circulating cell-free DNA (cfDNA), offers opportunities for real-time monitoring that could significantly impact on patient outcome. The presence of CTCs in the blood is a poor prognostic indicator, however these cells are often found at very low concentrations in the blood of patients with metastatic breast cancer (MBC), and this presents a significant technical challenge. Four CTC enrichment technologies were evaluated and compared with the "gold standard" CellSearch®, for the recovery of BC cell-lines from blood. No technique recovered higher numbers of BC cells than CellSearch®, however one antigen-independent method, ParsortixTM, showed promise by capturing cells that showed features of having undergone an epithelial-mesenchymal transition (EMT), which are not routinely detected by CellSearch®. In single blood samples collected from 194 MBC patients at various stages of treatment, total plasma cfDNA levels were compared with CellSearch® CTC counts, and levels of serum cancer antigen 15-3 (CA15-3) and alkaline phosphatase (ALK-PHOS), for the prediction of disease response. Total cfDNA level was the strongest predictor of disease response suggesting that cfDNA quantification may provide an additional, simple and inexpensive test for the monitoring of disease response in patients with MBC. By analysis of 5 MBC patients with high CTC counts by CellSearch®, next generation sequencing (NGS) of ~2200 mutations in 50 cancer genes, results showed not only mutational heterogeneity between single CTCs, but also that matched cfDNA samples accurately reflected the mutational profile of CTCs analysed. Together, these results demonstrate that both CTCs and cfDNA reflect the genetic status of the tumour, and are promising, non-invasive tools for the monitoring of disease response and detection of clinically-relevant somatic mutations in MBC patients.