In general, the epidemiological data from variola major outbreaks before and during the eradication era appear to support thecurrent view that vaccination prior to 3 days post-exposure willprovide benefit in preventing smallpox disease in exposed personsregardless of prior vaccination status. In addition, it appears thatpost-exposure vaccination given prior to the appearance of rashaffords clinical or survival benefit, but these benefits diminish whenvaccine is administered greater than one-week post-exposure.However, it is important to note that these data are limited in manyways.During this period only 1st generation vaccines were used; priorimmunity in individuals within the population (whether from pre-vious vaccination or exposure) may be underestimated; underlyingimmune issues of patients are unknown; specific descriptions (i.e.Rao’s classification) of the clinical presentation of index patientsand contacts that develop disease are not included; vaccine qualityand administration differences may be present as vaccine qualityprior to 1971 was largely uncontrolled and the bifurcated needlewas not recommended until 1968 [47,48]. Additionally, patientdemographics as well as social/cultural/economic differences arealso not always identified. Any one of these missing pieces ofinformation could help explain the variability among – and affectinterpretation of – these studies. Consequentially, our conclusionsare tempered with the understanding that these patients are pre-sumed to be naïve when given post-exposure vaccination, arepresumed to be immunocompetent, are presumed to be exposed tosufficient VARV to cause infection and disease, and are presumedto have been given a quality vaccine using appropriate adminis-tration routes. These presumptions and data gaps make it difficultto interpret the true efficacy of post-exposure vaccination. In theabsence of human smallpox disease, surrogate models offer ourbest chance of defining when post-exposure vaccination will pro-vide a survival benefit. The next section of this review will examinethe limited literature regarding post-exposure vaccination studiesin surrogate models.