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This review focuses on the novel approaches for exploring ccfNAs as epigenetic biomarkers in personalized clinical diagnosis and prognosis, their potential as therapeutic targets and disease progression monitors, and reveals the tremendous potential that epigenetic biomarkers present to improve precision medicine. We explore the latest techniques for both quantitative and qualitative detection of epigenetic modifications in ccfNAs. The data on epigenetic modifications on ccfNAs are complex and often milieu-specific posing challenges fo