Transmissible spongiform encephalopathies (TSEs or prion diseases) are neurological disorders associated with the aggregation of a pathologic isoform of a host-encoded protein, termed prion protein (PrP). The pathologic isoform of PrP, termed PrP(Sc), is a major constituent of the infectious agent. TSE diseases are characterized by neurodegenerative failure and inevitable morbidity. Bovine spongiform encephalopathy (BSE) has been transmitted from cattle to humans to cause a new variant of Creutzfeldt-Jakob syndrome. The potential for chronic wasting disease to similarly cross the species barrier from cervids to humans is considered unlikely but possible. Thus, understanding how TSE agents overcome resistance to transmission between species is crucial if we are to prevent future epidemics. The species barrier usually can be abrogated to varying degrees in laboratory animals. Studies done with transgenic animals, tissue culture, and cell-free assays established PrP as being necessary for TSE pathogenesis and illustrated that certain amino acid residues are more influential than others for conferring resistance to TSE agent transmission. The essence of what constitutes a TSE agent's species compatibility is thought to be orchestrated by a complex interplay of contributions from its primary amino acid sequence, its glycoform patterns, and its three-dimensional structure.