The zebrafish model organism is increasingly used for assessing drug toxicity and safety and numerous studies confirm that mammalian and zebrafish toxicity profiles are strikingly similar. This transparent vertebrate offers several compelling experimental advantages, including convenient drug delivery and low cost. Although full validation will require assessment of a large number of compounds from diverse classes, zebrafish can be used to eliminate potentially unsafe compounds rapidly in the early stages of drug development and to prioritize compounds for further preclinical and clinical studies. Adaptation of conventional instrumentation combined with new nanotechnology developments will continue to expand use of zebrafish for drug screening.