Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with ‘ctDNA relapse’, a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.