Scientifically known as Variola major, the deadliest form of smallpox has plagued mankind since time immemorial. This text chronicles the worldwide effects of the killer disease, with particular emphasis on the 19th and 20th centuries, including the devastations of the speckled disease during great armed conflicts. Specific attention is paid to the development and utilization of Dr. Edward Jenner's vaccination, chronicling the anti-vaccination movement, the evolving concept of compulsory vaccination and the global march toward eradication. Legal and moral challenges, the National Vaccine Institute, the treatment of American Indians and African Americans, immigrants, the often bloody quarantine battles, germ warfare, superstitions and home remedies are addressed from the historical perspectives of those who lived through and those who died of this scourge.