The process of discovering a drug is extremely time consuming and expensive, requiring extensive biochemical screening assays on cells and animal models of human diseases. Small organisms such as Caenorhabditis elegans (worm), Drosophila melanogaster (fruit fly), and Danio rerio (zebrafish) are among the top models used for investigation of disease pathology and the search for therapeutics. These model organisms offer many advantages including simplicity, genetic homology to humans, body transparency, and amenability to genetic manipulation which are desirable for investigation of various neurobehavioral processes in a whole biological system. However, the conventional manual or equipment-intensive methods for organism-based assays are slow, low-throughput and mostly qualitative, due to the lack of technologies to facilitate automation, control and quantitative analysis on these models. In this chapter, we will review the microsystems developed to date for worm, fruit fly, and zebrafish studies with a focus on providing basic information about these model organisms, followed by an introduction of microfluidic devices developed for studying the organisms’ neuronal and behavioral responses to various environmental cues such as chemicals, electrical signals, mechanical forces and light, to name a few. It is anticipated that these microfluidic devices will play a major role in facilitating fundamental disease investigations and drug discovery assays involving small-scale model organisms.