Smallpox, the worst infectious disease mankind has known, represents a major triumph as the first disease to be intentionally and completely removed from the human population. Although the disease was eradicated in 1980, the variola virus remains preserved in frozen stocks stored in two secure laboratories and there has been debate about whether these remaining stocks should be retained or destroyed. This case study introduces the history, biology, and bioethics of smallpox by having students decide to retain or destroy the smallpox stocks and generate questions about what they would need to know to make a more informed decision. Students explore the historical impact of the disease and why variola was such a dangerous pathogen. The case also details our successive victories against the disease, from the practice of variolation, to Edward Jenner's discovery of vaccination, culminating with the worldwide eradication effort. This leads to discussion of why smallpox was a candidate for eradication and the challenges that had to be overcome. The case is suitable for high school biology, undergraduate courses in microbiology, or any course where the history of science/medicine or bioethics is emphasized.