The content and design scheme for a readily adaptable, research-based laboratory course in chemical biology are presented. In this course, students interrogate protein structure and function using the site-specific incorporation of noncanonical amino acids by genetic code expansion. The relatively new field of genetic code expansion enables protein engineering with a diverse array of chemical functional groups. In this quarter or semester research-based undergraduate laboratory experience, student teams design, synthesize, and evaluate the structure-function relationships of proteins containing noncanonical amino acids on the basis of a self-selected hypothesis and then communicate their results in a formal manuscript and research presentation. The flexibility and versatility of genetic code expansion and this course structure empower students to engineer novel biomolecules and highlight the use of organic-chemistry principles for interrogating proteins. Generating noncanonical protein variants that have never been produced previously exposes students to novel research and trains them in essential basic biochemistry skills. This research-based undergraduate laboratory course can easily be adapted, scaled, and implemented on the basis of the interests, demographics, and resources of a given institution.