Liquid biopsy has entered a phase where clinical responsibility must match technological capability. Key challenges include pre-analytical standardization, large-scale prospective validation, and multi-analyte integration. AI-driven interpretation is becoming essential but must be clinically explainable and transparent. Early detection does not universally translate into survival benefit for all cancer types. Risk–benefit balance, overdiagnosis, and cost-effectiveness must be critically assessed. Liquid biopsy should be viewed as a decision-support tool rather than a standalone diagnostic authority. Its ultimate goal is improvement of survival and quality of life. This chapter outlines the future trajectory of liquid biopsy in precision medicine. It emphasizes a shift from technology-centered innovation to clinically grounded implementation.