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Cleaning validation has undergone a significant paradigm shift over the past three decades, evolving from prescriptive, arbitrary acceptance criteria to sophisticated risk-based methodologies grounded in toxicological science. This comprehensive review traces the evolution of cleaning validation practices from their inception in the late 1980s through the current era of health-based exposure limits. The transformation has been driven by regulatory advancements, including the United States Food and Drug Administration's (FDA) early guidance documents, the International Council for Harmonisation (ICH) quality guidelines (Q9, Q10, Q12), and the European Medicines Agency's (EMA) landmark 2014 guideline on setting health-based exposure limits. This review examines the transition from traditional acceptance criteria based on fractions of therapeutic doses and analytical detection limits to scientifically justified limits derived from Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE) values. Risk assessment methodologies including Failure Mode and Effects Analysis (FMEA), Hazard Analysis and Critical Control Points (HACCP), and risk ranking tools are critically evaluated for their application in cleaning validation programs. The mathematical frameworks for calculating Maximum Allowable Carryover (MACO) using both traditional and health-based approaches are presented and compared. Analytical method considerations, including Total Organic Carbon (TOC) analysis, High-Performance Liquid Chromatography (HPLC), and swab recovery validation, are discussed within the context of risk-based strategies. Implementation challenges, including equipment grouping, worst-case selection, and lifecycle management, are addressed. The review concludes with an examination of emerging trends, including the integration of Quality Risk Management (QRM) principles, continuous process verification, and the application of data integrity requirements to cleaning validation documentation. This evolution represents a maturation of pharmaceutical quality systems toward science-based and patient-focused manufacturing practices.