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The development of new biomaterials and drug delivery systems necessitates animal experimentation to demonstrate biocompatibility and therapeutic efficacy. Reduction and replacement of the requirement to conduct experiment using full-grown animals has been achieved through utilising zebrafish embryos, a promising bridge model between in vitro and in vivo research. In this review, we consider how zebrafish embryos have been utilised to test both the biocompatibility of materials developed to interact with the human body and drug release studies. Furthermore, we outline the advantages and limitations of this model and review legal and ethical issues. We anticipate increasing application of the zebrafish model for biomaterial evaluation in the near future. STATEMENT OF SIGNIFICANCE: This review aims to evaluate the potential application and suitability of the zebrafish model in the development of biomaterials and drug delivery systems. It creates scientific impact and interest because replacement models are desirable to the society and the scientific community. The continuous development of biomaterials calls for the need to provide solutions for biological testing. This review covers the topic of how the FET model can be applied to evaluate biocompatibility. Further, it explores the zebrafish from the wild-type to the mutant form, followed by a discussion about the ethical considerations and concerns when using the FET model.