Abstract: Spiroplasma biofilm formation explains the role of these wall-less bacteria in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Spiroplasma embedded in the biofilm polysaccharide matrix are markedly resistant to physical and chemical treatment, simulating the biologic properties of the TSE agent. Microcolonies of spiroplasma embedded in biofilm bound to clay are the likely mechanism of lateral transmission of scrapie in sheep and chronic wasting disease in deer via soil ingestion. Spiroplasma in biofilm bound to the stainless steel of surgical instruments may also cause iatrogenic transmission of Creutzfeldt-Jakob disease. Sessile spiroplasma in biofilm attach to the surface by curli-like fibrils, a functional amyloid that is important for spiroplasma entering cells. Curli fibers have been shown to interact with host proteins and initiate formation of a potentially toxic amyloid that multiplies by self-assembly. In TSE, this mechanism may explain how spiroplasma trigger the formation of prion amyloid. This possibility is supported by experiments that show spiroplasma produce α-synuclein in mammalian tissue cultures. The data linking spiroplasma to neurodegenerative diseases provide a rationale for developing diagnostic tests for TSE based on the presence of spiroplasma-specific proteins or nucleic acid. Research efforts should focus on this bacterium for development of therapeutic regimens for Creutzfeldt-Jakob disease.