AbstractModel‐based design of experiments (MBDOE) assists in the planning of highly effective and efficient experiments. Although the foundations of this field are well‐established, the application of these techniques to understand cellular processes is a fertile and rapidly advancing area as the community seeks to understand ever more complex cellular processes and systems. This review discusses the MBDOE paradigm along with applications and challenges within the context of cellular processes and systems. It also provides a brief tutorial on Fisher information matrix (FIM)‐based and Bayesian experiment design methods along with an overview of existing software packages and computational advances that support MBDOE application and adoption within the Systems Biology community. As cell‐based products and biologics progress into the commercial sector, it is anticipated that MBDOE will become an essential practice for design, quality control, and production. WIREs Syst Biol Med 2013, 5:181–203. doi: 10.1002/wsbm.1204This article is categorized under: Models of Systems Properties and Processes > Cellular Models Biological Mechanisms > Cell Signaling Analytical and Computational Methods > Computational Methods