The prion protein PRNP has been centrally implicated in the transmissible spongiform encephalopathies (TSEs), but its normal physiological role remains obscure. We highlight emerging evidence that PRNP displays antimicrobial activity, inhibiting the replication of multiple viruses, and also interacts directly with Alzheimer's disease (AD) amyloid-β (Aβ) peptide whose own antimicrobial role is now increasingly secure. PRNP and Aβ share share membrane-penetrating, nucleic acid binding, and antiviral properties with classical antimicrobial peptides such as LL-37. We discuss findings that binding of abnormal nucleic acids to PRNP leads to oligomerization of the protein, and suggest that this may be an entrapment and sequestration process that contributes to its antimicrobial activity. Some antimicrobial peptides are known to be exploited by infectious agents, and we cover evidence that PRNP is usurped by herpes simplex virus (HSV-1) that has evolved a virus-encoded 'anti-PRNP'.unction. These findings suggest that PRNP, like LL-37 and Aβ, is likely to be a component of the innate immune system, with implications for the pathoetiology of both AD and TSE.