Immunization procedures against Variola virus, from the historical perspective most often first credited to Edward Jenner in the late 18th century, helped finally to eradicate smallpox from the world. Since its eradication, the study of this disease and its pathology has been given little attention; however, with the emergence of Monkeypox virus into the human population and the potential use of smallpox as a bioterrorist weapon, the need for an option to vaccinate the world’s population is once again a reality. The vaccines used during the eradication program were live, attenuated Vaccinia virus preparations of varying virulence that caused a significant number of adverse reactions in naive subjects. Currently, immunosuppressed individuals, persons with certain skin diseases, and people with cardiovascular complications are contraindicated against receiving this type of vaccine. A new vaccine is needed. Until now, the only known correlate of immunity to the smallpox vaccine conveying protection has been the development of a scar at the site of vaccination. Characterizing the protective immune response established upon vaccination with Dryvax®, at both the innate and adaptive levels, would greatly enhance our understanding of the human immune response to the vaccine, and thus generate information for the production and evaluation of new and safer third- and fourth-generation vaccines.