The CATALYST program, initiated by the Advanced Research Projects Agency for Health (ARPA-H), seeks to develop AI/ML-enabled in silico human physiology modeling platforms for ADME-Tox simulation, aiming to replace ineffective preclinical animal testing methods. The program is structured in two phases over 54 months: Phase I focuses on technology development and qualification, while Phase II emphasizes regulatory adoption of the developed methodologies in IND applications. Key technical areas include data discovery methods, living systems tools, and in silico modeling. The CATALYST initiative addresses significant shortcomings in current drug development practices, where traditional animal testing often fails to predict human outcomes, resulting in a low success rate for therapeutics during clinical trials. By integrating diverse human-relevant data and utilizing advanced computational approaches, CATALYST aims to improve the accuracy, efficiency, and safety of drug development, ultimately leading to faster regulatory approvals and more effective treatments for diverse populations. The program also emphasizes ethical considerations, ensuring inclusivity in clinical trial designs and promoting equity in drug development processes. By generating robust predictive models, the CATALYST program endeavors to revolutionize the pharmaceutical landscape, ultimately advancing patient safety and health outcomes.