Circulating tumour DNA (ctDNA) represents an increasingly important biomarker for the screening, diagnosis and management of patients in clinical practice in advanced/metastatic disease across multiple cancer types. In this context, ctDNA-based comprehensive genomic profiling is now available for patient management decisions, and several ctDNA-based companion diagnostic assays have been approved by regulatory agencies. However, although the assessment of ctDNA levels in Phase II-III drug development is now gathering momentum, it remains somewhat surprisingly limited in the early Phase I phases in light of the potential opportunities provided by such analysis. In this perspective review, we investigate the potential and hurdles of applying ctDNA testing for the inclusion and monitoring of patients in phase 1 clinical trials. This will enable more informed decisions regarding patient inclusion, dose optimization, and proof-of-mechanism of drug biological activity and molecular response, thereby supporting the evolving oncology drug development paradigm. Furthermore, we will highlight the use of cost-efficient, agnostic genome-wide techniques (such as low-pass whole genome sequencing and fragmentomics) and methylation-based methods to facilitate a more systematic integration of ctDNA in early clinical trial settings.