Zebrafish as a vertebrate animal model is increasingly used for in vivo drug discovery and for assessing drug toxicity and safety.Numerous studies confirm that mammalian and zebrafish physiology,development,metabolism and pathways are strikingly similar and zebrafish is extremely predictive of mammalian responses.This convenient and predictive animal model offers several compelling experimental advantages including transparency,high throughput,short test period,low cost,small amount of compound required,easy manipulation and direct compound delivery,et al.FDA and EMEA have accepted zebrafish toxicity and safety assessment data for IND approval and more than one dozen of new drugs including natural products discovered primarily based on zebrafish model are now in clinical trials.In this reivew,we will introduce: ① the background of zebrafish-based natural product drug discovery; ② zebrafish models for assessing natural product toxicity and safety including acute toxicity,LC50,development toxiciy & teratogenicity,cardiovascular toxicity,liver toxicity,nerve toxicity,behavior toxicity,blood toxicity,anaphylactoid reaction and so on; ③ zebrafish models of human diseases for natural product drug discovery including anti-and pro-angiogenesis models,cancer models,cardiovascular disease models,CNS disease models,liver and metabolic disease models,inflammatory and bone disease models,and so on; ④ zebrafish models and assays for traditional Chinese medicine(TCM),TCM biologically quality control,TCM processing optimization and native Chinese herb identification.Zebrafish drug discovery platform can reduce the time and cost required for the natural product drug development process.