For clinical application, liquid biopsy technologies must undergo systematic validation beyond technical feasibility. This process follows the guided framework, which consists of analytical validity, clinical validity, and clinical utility. Analytical validity ensures accurate, precise, and reproducible measurement of the analyte. Clinical validity establishes a statistically meaningful association between the biomarker and disease status. Clinical utility demonstrates that test results lead to improved clinical decision-making or patient outcomes. Because liquid biopsy targets ultra-low abundance analytes, validation requirements are particularly stringent. Regulation mandate evidence across all three domains for approval for market. Failure at any stage can prevent clinical implementation despite technical innovation. This chapter outlines the regulatory and scientific principles governing liquid biopsy development.