The weight of evidence suggests that fine particle aerosols were the most frequent and effective mode of smallpox transmission because this would explain the relatively low mortality after variolation, the rarity of transmission by fomites, resolve the paradox of mucosal infection, and be consistent with "smallpox handler's lung" and with animal and virus aerosol experimental data. Certainly other modes of transmission occurred; fullblown disease could result from inoculation through the skin, the nasal mucosa, or the conjunctiva. Thus, smallpox cannot be classified as an "obligate" airborne infectious disease, such as tuberculosis (Riley et al., 1995) (sometimes referred to as a "true" airborne infection), because it was capable of initiating disease via infection of tissues outside of the lower respiratory tract. However, smallpox also cannot be classified as an isotropic infection (formerly termed "opportunistically" airborne infectious disease) because it appeared not to have been transmitted with equal effectiveness and virulence by all routes, whether aerosol, large droplet, or direct contact and skin inoculation. Smallpox appears to have been most effectively and virulently transmitted by fine particle aerosols and therefore should be classified as an anisotropic infection; an infection where route of transmission influences either virulence and or probability of infection, formerly called a "preferentially" airborne infectious disease.