ISO 15189, the international standard developed by the International Organization for Standardization (ISO) for medical laboratories, outlines the quality and competence requirements necessary for producing valid and reliable test results. Since its inception, ISO 15189 has undergone significant revisions to reflect evolving quality paradigms, technological advances, and increasing emphasis on patient safety. The 2022 revision introduces substantial changes from the 2012 version, incorporating risk-based thinking, integration with ISO 9001 and ISO/IEC 17025, and a stronger focus on continual improvement and patient-centered outcomes. This chapter offers a comprehensive comparison between ISO 15189:2012 and ISO 15189:2022, analyzing the rationale, implications, and implementation strategies for medical laboratories transitioning to the new standard.