This gripping narrative traces the history of the efforts to eradicate smallpox in the 1970s, the top-level decisions to keep a few vials of it for emergency purposes in American and Soviet freezers, and the reemergence of smallpox not only as a health threat, but as a potential bioweapon of unequaled destructive power. Preston details maverick natural cases that surfaced after worldwide eradication efforts, how it was discovered that undocumented reserves of smallpox were not only being kept, but researched and possibly "weaponized," and how hotly, in the US, teams of scientists and military intelligence personnel debated funding new smallpox research in the US with a view to developing a new vaccine as a defense.

The ethical issues in those debates are unprecedented in the scope of the possible public health threat and the variables that might make traditional vaccination ineffective against the weaponized virus. As in his previous books on biological threats, The Hot Zone and The Cobra Event (see annotation), Preston follows the work and lives of several key scientists and includes scenes from interviews with a variety of persons involved in confronting the political, ethical, and medical dilemmas posed by smallpox research and efforts to track and control it.