The potential for circulating tumour cells (CTCs) in the bloodstream to provide non-invasive access to biological material derived from primary (and secondary) tumour sites has led to considerable research into the feasibility, applicability and utility of such ‘liquid biopsies.’ Significant challenges remain in terms of: enriching or isolating CTCs; verifying their origin; determining their predictive power as proxies for the tumour bulk; and, expanding them in culture to provide patient-specific models for research. Perhaps the most significant question is whether the number of CTCs in the blood has prognostic significance, especially in the light of observations that the CTC burden can alter in response to various therapies [1, 2]. Increased CTC numbers could indicate successful ablation of the tumour bulk while simultaneously indicating increased metastatic risk [2]. We have embarked on an observational clinical trial to specifically determine how CTC numbers change during the course of radiotherapy for patients with non-small cell lung cancer (NSCLC) and how these numbers correlate with treatment response and clinical outcomes for these patients. The trial is using direct observation of cells from the blood, as well as enrichment of CTCs by negative-selection, CTC culture, CTC mRNA profiling, evaluation of circulating tumour DNA, and coagulation studies. CTCs are being characterised and counted by immunofluorescent staining using panels of haematological, epithelial and mesenchymal markers, in parallel with standard cytopathology staining, both evaluated by virtual microscopy of digitised slides. This approach allows rapid turnaround, potentially enabling real-time feedback of treatment response during the course of radiotherapy, which is particularly useful when evaluating newer radiotherapy modalities such as stereotactic ablative radiotherapy (SABR). An outline of the trial design and methods will be presented along with early results of the acquired CTC data.