The article by Robert M. Califf discusses the critical role of biomarkers in the development of medical diagnostics and therapeutics, highlighting the ongoing confusion regarding their definitions and applications. The U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have recently established a set of definitions for different types of biomarkers, which are crucial for their use in patient care, clinical research, and therapeutic development. The article explores the distinctions between biomarkers and clinical outcome assessments (COAs), and provides detailed definitions and applications for diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers. It also addresses the challenges and potential benefits of complex composite biomarkers, digital biomarkers derived from sensors and mobile technologies, and biomarker-driven predictive toxicology and systems pharmacology. The author emphasizes the importance of ensuring the quality and reproducibility of the science underlying biomarker development and fostering collaboration across the entire ecosystem of medical product development to advance rational, evidence-based biomarker development.The article by Robert M. Califf discusses the critical role of biomarkers in the development of medical diagnostics and therapeutics, highlighting the ongoing confusion regarding their definitions and applications. The U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have recently established a set of definitions for different types of biomarkers, which are crucial for their use in patient care, clinical research, and therapeutic development. The article explores the distinctions between biomarkers and clinical outcome assessments (COAs), and provides detailed definitions and applications for diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers. It also addresses the challenges and potential benefits of complex composite biomarkers, digital biomarkers derived from sensors and mobile technologies, and biomarker-driven predictive toxicology and systems pharmacology. The author emphasizes the importance of ensuring the quality and reproducibility of the science underlying biomarker development and fostering collaboration across the entire ecosystem of medical product development to advance rational, evidence-based biomarker development.