Teaching methods of genetic analysis such as fluorescence in situ hybridization (FISH) can be an important part of instructional units in biology, microbiology, and biotechnology. Experience, however, indicates that these topics are difficult for many students. The authors of this article describe how they created an activity that effectively simulates FISH using a paper model and fluorescent dyes. This hands-on procedure is designed for use as either a laboratory or classroom exercise. Instructors may use the templates provided or create their own. Research has shown that adapting manipulatives to fit topics being presented enhances instruction, student satisfaction, and understanding. The purpose of this activity is to promote both content mastery and critical thinking through self-discovery. In the process, students will: (1) improve their scientific reasoning and communication skills; (2) generate and test ideas about FISH; (3) explain how the assay is used for gene mapping and identifying chromosomal abnormalities; and (4) draw conclusions and communicate their reasoning. This activity is considered non-hazardous, but regular safety procedures should be followed when using these materials. Since research has demonstrated that instruction effectiveness is enhanced when incorporating materials that actively engage students interest in generating scientific explanations, the present exercise allows them to model the FISH technique using readily-available resources, giving them, as one student noted, the visualization they need. A list of Internet Resources and NABT Organizational Members are included. (Contains 3 figures and 2 tables.)