The last several years have marked a noticeable shift in our perception of the prion replication mechanism. According to the ‘‘cloud’’hypothesis, pools of infectious isoform of prion protein (PrPSc) within individual strains or isolates are intrinsically heterogeneous; the heterogeneity presumably arises due to spontaneous variation in PrPSc structure [1, 2]. Upon changes in the replication environment, minor variants that fit best to replicate in the new environment receive selective advantages. Consistent with this view, a growing number of studies have highlighted the fact that prion strains exhibit high levels of conformational plasticity and are subject to transformation when exposed to new replication environments. Drug-resistant prions were found to emerge in cultured cells following treatment with prion inhibitors swainsonine or quinacrine [2, 3]. Studies by Weissmann’s group showed that cloned prion strains accumulate PrPSc variants quite quickly, presumably due to ongoing processes of spontaneous ‘‘mutations’’of PrPSc structure [2]. What are the origins of strain mutation and how do prions mutate? According to the ‘‘cloud’’hypothesis, changes in replication environment might give selective advantage to minor PrPSc variants that are already present in the PrPSc pool [1]. However, the origin of minor variants is not clearly specified (Figure 1A).