PURPOSE OF REVIEW: Prion diseases continue to present a diagnostic and therapeutic challenge to clinicians and researchers worldwide. Many important aspects of prion biology remain unclear, and we still do not understand the nature of the infectious agent, the mechanisms leading to central nervous system damage, and the physiological function of the cellular prion protein. The current diagnostic tools for prion infections are breathtakingly insensitive when compared with those of other infectious diseases. Finally, there are hardly any therapeutic strategies. However, not all is gloomy, and many recent developments have advanced our basic understanding of prion diseases. RECENT FINDINGS: In most prion infections, the portal of entry is extraneural. Although we still do not understand all details, several molecules and cell types have been identified as key players in prion neuroinvasion. These include lymphotoxins and their receptors, follicular dendritic cells, and the autonomic nervous system. These advances in knowledge are spurring the exploration of strategies for postexposure prophylaxis. SUMMARY: The prion phenomenon is, at the same time, the cause of horrible diseases, and a fascinating biological enigma. The scope of this review is to discuss a selection of novel findings in prion research.