The gut plays a key role in drug absorption and metabolism of orally ingested drugs. Additionally, the characterization of intestinal disease processes is increasingly gaining more attention, as gut health is an important contributor to our overall health. The most recent innovation to study intestinal processes in vitro is the development of gut-on-a-chip (GOC) systems. Compared to conventional in vitro models, they offer more translational value, and many different GOC models have been presented over the past years. Herein, we reflect on the almost unlimited choices in designing and selecting a GOC for preclinical drug (or food) development research. Four components that largely influence the GOC design are highlighted, namely (1) the biological research questions, (2) chip fabrication and materials, (3) tissue engineering, and (4) the environmental and biochemical cues to add or measure in the GOC. Examples of GOC studies in the two major areas of preclinical intestinal research are presented: (1) intestinal absorption and metabolism to study the oral bioavailability of compounds, and (2) treatment-orientated research for intestinal diseases. The last section of this review presents an outlook on the limitations to overcome in order to accelerate preclinical GOC research.