Variola- and alastrim field strains obtained from recent epidemics in India and Africa were inoculated and submitted to passages through heterologous host system in an attempt to obtain transformation into vaccinia virus. We studied in a similar manner variola virus strains cultivated in the embryonated egg, the mouse, and in tissue culture cells. Ruminants, pigs, monkeys, rabbits, eggs and various tissue cultures were used for this purpose. By none of these methods did we obtain a successful transformation of the variola- or alastrim virus into vaccinia virus. The observation of the behaviour of the variola and alastrim virus in the various host systems showed two distinct groups. The first group comprises the embryonated egg, the infant mouse, a number of tissue cultures and the monkey. The variola and alastrim viruses showed good adaptation to these hosts, as well as readiness to undergo an unlimited number of passages without modification of their original properties. We placed the rabbit, the pig and the ruminants into a second group. Although the inoculation of variola and alastrim virus to these hosts was occasionally followed by pathological reaction at the site of inoculation,. the attempts to carry on further virus passages and to obtain transformation was unsuccessful. Our efforts to transmit variola virus from the different hosts of group I to the animals of group II were unsuccessful. The successful experiments reported previously in the literature regarding the transformation of variola and alastrim virus into vaccinia virus are discussed. A new hypothesis is devised concerning the origin of the vaccinia virus.