<p>Cancer screening is an essential public health intervention for diagnosing cancers at an early stage that can enable earlier treatment — ideally with curative intent — and thus lead to improved outcomes. Over the past decade, liquid biopsy-based tests have emerged as a promising, minimally invasive and broadly applicable screening approach by combining multi-cancer early detection (MCED) with tumour tissue-of-origin identification. Large-scale randomized clinical trials evaluating liquid biopsy-based MCED approaches are now under way, although whether the diagnostic performance of this first generation of MCED tests is sufficient to translate into clinical benefits remains to be determined. In this Review, we discuss the promises and pitfalls of current MCED tests and highlight possible trajectories for the field of early cancer detection.</p>