A scientific theory or hypothesis is presented, in which mineral particles may play a pivotal role in the prion disease transmissible spongiform encephalopathy (TSE), and possibly also in other protein-misfolding diseases. Montmorillonite clay (Mte) and other minerals are known to bind to scrapie prion protein (PrP-Sc) in soil. The hypothesis is explored that, in transmissible spongiform encephalopathy, Mte or other mineral particles, upon contact with lipids, such as in the gut or at the cell plasma membrane, may interact with lipids or with lipid rafts. The minerals may catalyze formation of lipid vesicles, and might also be capable of inducing lipid raft clustering or other lipid raft or plasma membrane changes. Some of these lipid vesicles or rafts might then contain or bind PrP-Sc, and sometimes also contain montmorillonite or the mineral catalyst. Mte-PrP-Sc or the affected lipid vesicles/particles could also promote PrP-C to PrP-Sc conversion by providing conditions for misfolding. These conditions provided for protein misfolding may include the following: multiple unique compartments providing sizes, shapes or aqueous/lipid environments that promote varied folding conformations, presence of an anion (Mte), negative-charge (Mte), lipid membrane mimetic (e.g. associated lipid particle, vesicle or raft), interaction with bound or contained PrP-Sc, presence of bound copper, and/or copper binding affinity. Mte-catalyzed lipid vesicles are proto-cell-like entities, making them potential candidates to be part of the infectious particle in prion disease, which can behave like an infectious organism but does not appear to depend on nucleic acid. Lipid vesicles or rafts may resemble endosomes, which would be consistent with reports of prion being transported and formed along an endosome-like pathway. Additionally, the vesicles or rafts could accumulate intra-cellularly, and might form tubulovesicular structures, which are hallmarks of prion disease. Potential applications of this theory to more common protein misfolding diseases, Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis, are discussed. This theory, which I term the mineral-lipid prion hypothesis, provides a basis for potential novel interventions in the field of prion and protein-misfolding diseases. In addition, this theory suggests that similar silicate- or mineral-catalyzed lipid vesicles/liposomes might be further explored as useful compartments that could be manipulated in order to deliver molecules or even proteins to or from cells.