Prions diseases are a group of fatal neurodegenerative disorders called the transmissible spongiform encephalopathies (TSEs), which include bovine spongiform encephalopathy in cattle, scrapie in sheep and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are associated with the conversion of normal cellular form of the prion protein (PrPC) to an altered pathological form (PrPSc). An important phenomenon known as the species barrier affects prion transmission, resulting in longer incubation time and lower incidence of disease upon transfer between species. Another feature of prion diseases is diseasemodulating polymorphisms in PrP sequence which can alter individual‟s susceptibility to infection. This thesis investigates two properties of PrP that may elucidate the mechanisms underlying both species barrier and disease resistance; (i) effect of diseasemodulating mutations on folding kinetics of PrP and (ii) impact of diseasemodulating mutations on formation of PrP fibrils. Equilibrium and kinetic folding studies demonstrate that the folding pathway of PrP is affected by mutation Q167R which confers disease resistance, and mutations S170N, N174T and S170N/N174T characteristic for Chronic Wasting Disease in cervids, which are known to increase disease susceptibility. The destabilising effect of Q167R mutation previously observed via equilibrium folding studies was confirmed through direct kinetic observations. Subsequent fibrilisation experiments suggested a possible link between the stability of mouse prion protein and its propensity to form fibrils, elucidating a potential mechanism of increased disease resistance conferred by Q167R mutation. Equilibrium folding studies of S170N, N174T and S170N/N174T revealed a surprising correlation between the structural effects of these mutations and fibrilisation propensity. Based on these findings, a disease resistance mechanism centred on decreased formation of neurotoxic particles in the organism as well as diminished ability of infectious oligomers from both inside and outside to propagate oligomerisation of PrP has been proposed.