The cellular prion protein (PrP C ) has emerged as an important copper binding protein. The interaction of copper with PrP C may play important roles in both the physiological function of the protein, and in the pathogenesis of prion diseases. The copper coordination chemistry of PrP C is complex, as different Cu(II) coordination modes can be formed depending on pH and copper to protein ratios, and involving six different His residues in the N-terminal region of the protein. The nature of these Cu(II) binding sites has been studied using theoretical tools, which expand on the information obtained from experimental results and provide important insights into Cu–PrP C interactions. This article provides a general overview of the different Cu(II) binding sites in PrP C and their redox properties, highlighting the contributions from electronic structure calculations and molecular dynamics simulations. Particular emphasis is placed in discussing the electronic structure of each Cu binding mode, as it is intimately related to redox properties. For most Cu binding modes, the dominating Cu(II) bonding interactions involve deprotonated amide nitrogens, which yield CuN amide bonds that are significantly more covalent than the CuN His bond. The key factors that determine the direction of Cu(II) binding to backbone amides in the vicinity of the anchoring His are discussed. Additionally, the impact of Cu–PrP C interactions in protein folding and in the potential initiation of PrP C aggregation is discussed.