The field of toxicology is undergoing a vast change with high-throughput (HT) approaches that rapidly query huge swaths of chemico-structural space for bioactivity and hazard potential. Its practicality is due in large part to switching from high-cost, low-throughput mammalian models to faster and cheaper alternatives. We believe this is an improved approach because the immense breadth of the resulting data sets a foundation for predictive structure-activity-based toxicology. Moreover, rapidly uncovering structure-related bioactivity drives better decisions about where to commit resources to drill down to a mechanism, or pursue commercial leads. While hundreds of different in vitro toxicology assays can collectively serve as an alternative to mammalian animal model testing, far greater efficiency and ultimately more relevant data are obtained from the whole animal. The developmental zebrafish, with its well-documented advantages over many animal models, is now emerging as a true biosensor of chemical activity. Herein, we draw on nearly a decade of experience developing high-throughput toxicology screens in the developmental zebrafish to summarize the best practices in fulfilling the better, faster, cheaper goals. We include optimization and harmonization of dosing volume, exposure paradigms, chemical solubility, chorion status, experimental duration, endpoint definitions, and statistical analysis.