Zebrafish represents a versatile model organism with many molecular, morphological, and physiological similarities to mammals. Importantly, zebrafish are readily susceptible to perturbations by small molecules, including numerous pharmaceuticals in clinical use. Given these qualities, plus their small size and transparency, zebrafish embryos can be utilized for large-scale phenotype-based screens for small-molecule modifiers of biological processes. Thus, in a manner analogous to classical genetic screens, zebrafish chemical screens have the potential to reveal novel insights into complex biological pathways, as well as to identify lead compounds for novel therapeutics.