This PowerPoint-driven case study with supporting supplemental materials is designed for students to learn about the protein p53 (the “guardian of the genome”) and how characteristic mutations in the protein were used to establish that smoking causes lung cancer. Students work through a series of activities in which they identify mutational hotspots and a mutational signature of tobacco exposure, and then use this information to make the case against big tobacco. Optional follow-up activities allow students to further explore the history of big tobacco, p53, and public health. Throughout the case study, students use actual p53 sequences from p53 databases, as well as authentic bioinformatics tools (e.g., blastp). The case reinforces many general education essential skills and concepts, including critical thinking, quantitative reasoning, and personal and social responsibility. It is suitable for advanced high school or AP biology, undergraduate introductory biology, or a course in public health where it could be used in conjunction with learning about smoking cessation interventions. It can be used in either a face-to-face or remote learning setting.