A short review of the results of molecular modeling of prion disease is presented in this chapter. According to the "one-protein theory" proposed by Prusiner, prion proteins are misfolded naturally occurring proteins, which, on interaction with correctly folded proteins may induce misfolding and propagate the disease, resulting in insoluble amyloid aggregates in cells of affected specimens. Because of experimental difficulties in measurements of origin and growth of insoluble amyloid aggregations in cells, theoretical modeling is often the only one source of information regarding the molecular mechanism of the disease. Replica exchange Monte Carlo simulations presented in this chapter indicate that proteins in the native state, N, on interaction with an energetically higher structure, R, can change their conformation into R and form a dimer, R(2). The addition of another protein in the N state to R(2) may lead to spontaneous formation of a trimer, R(3). These results reveal the molecular basis for a model of prion disease propagation or conformational diseases in general.