A plethora of prion strains can be propagated indefinitely in hosts homozygous for the PrP gene. Within the framework of the “protein-only” hypothesis, the strain-specific properties are enciphered in the conformation of the strain-associated PrPSc. Are these conformations codetermined by additional components, whose presence or absence within an infected cell could define the cell’s competence to replicate a particular strain? Which cellular components, if any, contribute to the PrPC-to-PrPSc conversion in the cell? Many questions still remain to be answered in the field launched and nurtured by Carlton Gajdusek, to whom this essay is dedicated.