Non-invasive genomic analysis of cancer can revolutionize the study of tumour evolution, heterogeneity, and drug resistance. Clinically applied, this can transform current practice in cancer diagnosis and management. Cell-free DNA in plasma contains tumour-specific sequences. This circulating tumour DNA (ctDNA) is a promising source of genomic and diagnostic information, readily accessible non-invasively. The study of ctDNA is therefore timely and of great importance. But it is also very challenging. Measurement can be complex, and high-quality samples are not easily obtained. Though progress has been made, much remains to be discovered.My lab pioneered the use of targeted sequencing to analyse mutations in ctDNA. We recently developed a ground-breaking paradigm for analysing evolving cancer genomes in plasma DNA, combining ctDNA quantification with exome-sequencing of serial plasma samples. Applied to extensive sets of clinical samples my lab has characterized, this will enable large-scale exploration of acquired drug resistance with unprecedented resolution. CancerExomesInPlasma aims to use ctDNA for genome-wide analysis of tumour evolution, as a means for non-invasive, unbiased discovery of genes and pathways involved in resistance to cancer therapy.