Liquid Biopsy: Past, Present, and Future

ABSTRACT Liquid biopsy has evolved over two decades from an extension of tissue genotyping into a minimally invasive approach for repeat and longitudinal molecular assessment across the cancer continuum. Advances in sequencing, digital PCR, error suppression, and computational analytics have expanded analytes beyond circulating tumor DNA and circulating tumor cells to extracellular vesicles, circulating RNAs, and tumor‐educated platelets, while broadening readouts from mutations to methylation, fragmentomics, transcriptomics, proteomics, and multiomic integration. This review traces the field from its technological foundations to current applications in early detection and multicancer early detection, therapy selection and resistance monitoring, minimal residual disease, recurrence‐risk stratification, and longitudinal response assessment across major cancers and selected nononcologic settings. We distinguish clinically established applications from emerging and exploratory strategies and emphasize that high analytical performance does not by itself establish clinical utility. We further discuss preanalytical handling, standardization, biological confounders, and evidence required for implementation. Future progress will depend on use‐case‐driven development, prospective utility studies, longitudinal and multimodal interpretation, and integration with established diagnostic pathways. Together, these priorities define a transition from molecular detectability toward reproducible, actionable, and clinically meaningful liquid biopsy.