Early detection of cancer is crucial to improve prognosis, and circulating tumour DNA (ctDNA) presents a minimally invasive screening tool. In contrast to mutation patterns, DNA methylation patterns in ctDNA resemble that of cancer tissue. Xu et al. showed that ctDNA methylation patterns can be used as biomarkers for diagnosis and prediction in hepatocellular carcinoma (HCC). Through analysis of differential methylation profiles in HCC tissues and blood leukocytes in healthy individuals, they identified a panel of methylation markers enriched in HCC. They successfully validated this panel in matched DNA from HCC tumour tissue and plasma. Using ctDNA from a cohort of 1,098 patients with HCC and 835 normal controls, the researchers developed diagnostic and prognostic prediction models. These models strongly correlated with tumour burden, stage and therapy response, and reliably predicted clinical outcomes.