There are many strains of scrapie, distinguishable by their disease characteristics in genetically-defined mice. Numerous distinct strains have been isolated in the same mouse strain, indicating that scrapie agents have an informational molecule, independent of the host. Strain characteristics are stable on serial mouse passage under constant passaging conditions. However, changes in the species or mouse genotype used for passage may lead to changes in properties which are consistent with the selection of variants which replicate faster in the new host, rather than active modification of the agent by the host. The fact that this has been observed with biologically cloned strains is evidence for mutation in the scrapie agent. Transmissions to mice from natural scrapie and BSE suggest that strain variation exists in the field. These findings have important implications when considering the molecular nature of the scrapie agent and the details of agent-host interactions.