01904nas a2200253   4500000000100000008004100001260001500042653000700057653001100064653002000075653002100095653003000116653002200146653001600168100001500184700001800199700002100217245007000238856007200308300001100380490000800391520123700399022001401636       2026                            d  c2026-09-0110aAI10aCRISPR10aorgan-on-a-chip10aDrug development10amicrophysiological system10apreclinical model10atherapeutic1 aRyan Posey1 aAlican Özkan1 aDonald E. Ingber00aHuman organ-on-a-chip technology as a catalyst for drug discovery  uhttps://www.sciencedirect.com/science/article/pii/S0169409X26001547  a1159200 v2363 aThe pharmaceutical industry currently faces a critical attrition crisis, with approximately 90% of drug candidates failing during clinical translation. A major contributor to this high failure rate is the inability of preclinical models, namely conventional cell cultures and animal studies, to accurately predict human responses. In recent years, human Organ-on-a-Chip (Organ Chip) microfluidic culture technology has emerged as an alternative and potentially transformative approach to overcome these limitations. Unlike static cell cultures or organoids, Organ Chips recapitulate organ-level pathophysiology by incorporating tissue–tissue interfaces, dynamic fluid flow, mechanical cues, and immune cells, enabling a higher level of physiological mimicry as well as the testing of therapeutic responses using clinically relevant drug pharmacokinetic profiles. In this article, we focus on how human Organ Chip technology has begun to be used to facilitate drug development, its advantages and disadvantages relative to traditional preclinical models, and its recent integration with artificial intelligence (AI) and high throughput screens, which have the potential to accelerate discovery while ameliorating translation rates.  a0169-409X