The existing scientific evidence that links animal and human TSEs is reviewed and discussed. The challenges involved in identifying TSEs as zoonoses are described and the example of the process that led to the establishment of a link between Bovine Spongiform Encephalopathy (BSE) and variant Creutzfeldt-Jakob Disease (vCJD) is reviewed. The strain diversity of animal and human TSE agents and the factors influencing the capacity of TSE agents to cross the species transmission barrier are also discussed. The scientific opinion critically assesses the tools and methodologies currently available to study and evaluate the possible association of animal and human TSEs, focussing on epidemiological and laboratory methods. The available scientific evidence on Classical BSE, Atypical BSE (H-type and L-type), Classical scrapie, Atypical scrapie, Chronic Wasting Disease (CWD), Transmissible Mink Encephalopathy (TME) and human TSEs is reviewed. The conclusions state that, at present, the only TSE agent demonstrated to be zoonotic is the Classical BSE agent. Active screening has allowed the identification of three new forms of animal TSEs (H-type Atypical BSE, L-type Atypical BSE and Atypical scrapie), but the information obtained has major limitations due to the unknown sensitivity of the current monitoring system for these TSEs. There is no epidemiological evidence to suggest that Classical scrapie is zoonotic. The epidemiological data are too limited to conclude whether the Atypical scrapie agent has a zoonotic potential. Transmission experiments to human PrP transgenic mice or primates suggest that some TSE agents other than the Classical BSE agent in cattle (namely L-type Atypical BSE, Classical BSE in sheep, TME, CWD agents) might have zoonotic potential and indicate that that of the L-type Atypical BSE agent appears similar or even higher than that of the Classical BSE agent. A single study reported efficient transmission of a natural sheep Classical scrapie isolate to primates.