Prion diseases are often caused by peripheral uptake of the infectious agent. To reach their ultimate target, the central nervous system (CNS), prions enter their host, replicate in lymphoid organs and spread via peripheral nerves. Once the agent has reached the CNS disease progression is rapid, resulting in neurodegeneration and death. many of these mechanisms have been uncovered using genetically modified mice. A recently published study demonstrated the presence of pathological prion protein in sympathetic ganglia of patients suffering from variant Creutzfeldt-Jakob disease, suggesting that these mechanisms might apply to humans.