01415nas a2200181   4500000000100000008004100001260001500042100001400057700001800071700001400089700002400103700001700127245007900144856005600223300001300279490000600292520093500298       2026                            d  c2026-04-161 aXuekun Wu1 aMatthew A. Wu1 aJames Zou1 aNicole Kleinstreuer1 aJoseph C. Wu00aReimagining human-centric drug development with new approach methodologies  uhttps://www.science.org/doi/10.1126/science.aeb0045  aeaeb00450 v03 aDespite unprecedented technological progress, most drug candidates continue to fail in clinical trials, reflecting a persistent gap between preclinical models and human biology. New approach methodologies (NAMs), by spanning human-derived cellular systems, microphysiological platforms, and artificial intelligence, offer a paradigm shift in human-centric drug development and biomedical research. Recent regulatory reforms, such as the US Food and Drug Administration (FDA) Modernization Act 3.0, have begun to position NAMs as a complement to or replacement for animal testing. This Review synthesizes emerging biological and computational NAMs and examines how their integration is reshaping drug development. We also discuss regulatory and ethical frameworks enabling this transition and outline a roadmap for embedding NAMs in a predictive, efficient, and ethically grounded infrastructure of human-centered drug development.