Cancers frequently develop resistance to anticancer therapies, but opportunities to obtain tissue samples for molecular analyses of resistance mutations are typically limited. Mohan et al. used high-throughput sequencing to analyse the tumour-derived DNA in the blood of ten patients with colorectal cancer who were undergoing treatment with epidermal growth factor receptor (EGFR)-targeted antibodies. They found that acquired focal amplifications (rather than point mutations) in genes that are known to be involved in the response to EGFR-targeted agents were predictive of therapeutic resistance. Such monitoring may aid optimization of treatment regimens.