The availability of recombinant prion proteins (recPrP) has been exploited as a model system to study PrP-mediated toxicity, conversion, and infectivity. According to the protein only hypothesis, the central event in the pathogenesis of prion diseases is the conversion of PrP(C) to PrP(Sc). This involves a dramatic increase in beta sheet conformation as PrP(C) is converted to PrP(Sc), and it is widely believed that this conformational change affects the as-yet undefined function of PrP(C). Although there are many methods available to monitor for the changes in the structural makeup of PrP mutants and oligomers formed with respect to disease relevance, circular dichroism is one of the most popular methods used. In this chapter, we discuss the fundamental principles of circular dichroism and its current role and applications in prion disease research.