The transmission of bovine spongiform encephalopathy to humans as variant Creutzfeldt-Jakob disease (vCJD) has focused public attention on how prion diseases are transmitted and how prions reach the brain after exposure. Prion diseases are characterised by transmissibility and neuropathological features of gliosis, neuronal loss and microscopic vacuoles, termed spongiosis. The principal component of prions is the glycoprotein PrPSc, which is a conformational modified isoform of the normal membrane protein PrPC. How are prions transmitted and how do prions find their way once they have been ingested? Prion models in mouse and hamster point to lymphoreticular cells which support an early replication phase of prions before reaching the central nervous system via peripheral nerves. Whilst some key players seem to have been identified so far, the mechanisms of prion propagation to the brain are still not fully understood. Seemingly contradictory results have led to some confusion and have provoked discussion.