Small molecule screens have become useful tools in ongoing efforts to understand complex biologic systems and disease states. These screens can identify compounds that specifically affect signaling pathways, development, and disease processes. The zebrafish Danio rerio has increasingly been used as a whole organism model in which to perform such functional small molecule screens. Here, we review recent advances in screening approaches that focus on modulation of developmental processes and signaling pathways, along with suppressor screens of disease models. The identification of small molecule targets continues to be a challenge, and several recent approaches to this problem are discussed. The promise of chemical screens in zebrafish to identify novel biologic probes and therapeutic compounds continues to drive this rapidly growing field.