The zebrafish has proven to be an invaluable vertebrate animal model for developmental biology. Recent technological advances have added an arsenal of tools to expand its use into the realm of drug discovery. This includes methodology to generate transgenic reporter lines that allow for the direct visualization of fluorescent markers in live embryos. With the addition of automated imaging and analysis of embryos treated with small molecules, these innovations have expanded its utility into high throughput chemical screens. This review will highlight some of these advances that have propelled zebrafish as a tool for drug discovery. Birth Defects Research (Part C) 90:185–192, 2010. © 2010 Wiley-Liss, Inc.