The in vitro conversion techniques in cell-free and cell culture systems have provided tools to adequately study the underlying mechanism of TSEs, namely PrP conversion. These systems also have provided tools that make it easier to study the interspecies and intraspecies transmissibilities of TSEs. Finally, these systems also may assist in the discovery of TSE therapeutic strategies and in the development of extremely sensitive TSE detection techniques. In vivo TSE transmission studies are limited to (transgenic) animals (mostly mice). Although the cell culture systems also are restricted in their species-range (mostly mouse), the currently used cell-free systems. Allow studying almost all possible species barriers (including the potential transmission of various TSEs to humans). One advantage of the cell culture systems, however, is that they generate do novo TSE infectivity. Studies using cell cultures also take into account several cofactors in addition to PrP that might be involved in replication the TSE agent. Although the in vitro systems provide accurate tools to study TSE agent parameters, they mainly or only focus on the molecular processes of PrP conversion. Other factors (i.e., host genetic factors [99]) that, for example, determine the differential uptake of the TSE agent from the environment, might play an additional role in determining the susceptibility of hosts for TSEs and on the transmission of the disease among individuals.