Zebrafish swimming towards cures: a scalable NAM platform for drug discovery

Drug discovery faces escalating costs, extended timelines, and ∼90% failure rates, prompting National Institutes of Health (NIH) and US Food and Drug Adminstration (FDA) guidance to reduce animal testing. As a New Approach Methodology (NAM), zebrafish (Danio rerio) bridges high-throughput in vitro assays and mammalian models. Its genetic tractability, optical transparency, rapid development, high fecundity, and genomic similarity to humans enable cost-effective whole-organism screening across drug development. In this review, we survey zebrafish applications from target identification to regulatory evaluation, and how advances in automation, imaging, artificial intelligence (AI), and genetic engineering are extending its reach. We highlight how zebrafish offer a complementary platform accelerating therapeutic discovery and precision medicine.