Cancer personalized profiling by deep sequencing (CAPP-Seq) is a novel economical and ultrasensitive method for quantitation of circulating tumour DNA (ctDNA) that promises to improve the routine detection and monitoring of many cancers. A form of the assay focused on somatic mutations associated with non-small-cell lung cancer (NSCLC) enabled the detection of ctDNA in 100% and 50% of patients with stage II–IV NSCLC and stage I NSCLC, respectively, with a specificity of 96%. In addition, levels of ctDNA detected using CAPP-Seq closely correlated with tumour volume before and during therapy, enabled assessment of therapeutic response earlier than was possible by imaging, and identified residual disease in cases of treatment-related imaging artefacts. The method could also be used to detect and genotype tumours without the need for biopsy, although improvements are needed to increase the sensitivity in stage I tumours.