The zebrafish (Danio rerio) is one of the most widely used research model organisms funded by the United States' National Institutes of Health, second only to the mouse. Here, we discuss the advantages and unique qualities of this model organism. Additionally, we discuss key aspects of experimental design and statistical approaches that apply to studies using the zebrafish model organism. Finally, we list critical details that should be considered in the design of zebrafish experiments to enhance rigor and data reproducibility. These guidelines are designed to aid new researchers, journal editors, and manuscript reviewers in supporting the publication of the highest-quality zebrafish research.