A key molecular event in prion diseases is the conversion of PrP (prion protein) from its normal cellular form (PrP(c)) into the disease-specific form (PrP(Sc)). The transition from PrP(c) to PrP(Sc) involves a major conformational change, resulting in amorphous aggregates and/or fibrillar amyloid deposits. Here, we review several lines of evidence implicating membranes in the conversion of PrP, and summarize recent results from our own work on the role of lipid membranes in conformational transitions of prion proteins. By establishing new correlations between in vivo biological findings with in vitro biophysical results, we propose a role for lipid rafts in prion conversion, which takes into account the structural heterogeneity of PrP in different lipid environments.