Prion disease is thought to be caused by changes in the conformation of normal cellular prion protein (PrPC) to an infectious PrPSc isoform, which induces neurotoxicity in PrPC-expressing cells. A physical interaction between PrPC and PrPSc stimulates this conformational change, so investigating PrP uptake and cellular localisation is crucial to obtain a better understanding of the pathology of prion disease. Roger Morris and colleagues previously reported that PrP binds to low-density lipoprotein receptor-related protein 1 (LRP1), which has two high-affinity ligand-binding sites (clusters 2 and 4). In a follow-up study (p. 246) they now show that both PrPC and PrPSc interact only with LRP1 ligand-binding cluster 4, and that PrPSc appears to out-compete PrPC for binding to this site. Furthermore, the kinetics and outcome of PrPSc endocytosis differ from that of PrPC: PrPSc is endocytosed more rapidly and targeted to lysosomes, whereas PrPC is recycled back to the cell surface. These differences, the authors propose, might be explained by differences in the size of the oligomers formed by the two PrP isoforms. As PrPSc binding and uptake is decreased by inhibiting the expression of LRP1, the authors propose that preventing the interaction between PrPSc and LRP1 ligand-binding cluster 4 might be effective for limiting prion disease.