A prion is a misfolded form of the cellular prion protein, PrPC. Although the role of PrP in neurodegeneration was established over 30 years ago, there is little understanding of the protein’s normal function, and how misfolding leads to profound disease. Recent work shows that PrPC coordinates the cofactors Cu2+ and Zn2+, and regulates the distribution of these essential metal ions in the brain. Moreover, these metals stabilize a previously unseen fold in PrPC, the observation of which provides new insight into the mechanism of prion disease. To date, Cu2+ coordination was thought to be limited to residues within the protein’s N-terminal domain. However, new NMR and EPR experiments suggest that histidine residues in the C-terminal domain assist in stabilizing the Cu2+-promoted PrPC fold. This talk will describe combined NMR, EPR, mutagenesis and physiological studies that provide new insight into the PrPC fold and function.