Since its discovery as an innate bacterial immune system, the clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (CRISPR-Cas9) system has quickly landed on mammalian genomes to become the first-in-class editing technique. CRISPR-Cas9 offered an inval­uable approach to correct pathogenic mutations, thus becoming a promising cure for diseases with highly unmet medical needs. To date, several attempts have been made to understand, categorize and predict the outcome of genetic manipulation with different degrees of success. The lack of an appropriate and translatable model to test CRISPR/Cas9 effects, both wanted and unwanted, has limited its applications to advance gene therapies. Herein we describe the potential of microphysi­ological systems (MPS) as an alternative to the classical models used in CRISPR safety studies, such as immortalized cell lines or small mammals (e.g., rodents), to facilitate the progress of new CRISPR medicines to the clinics.