Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species caused by prions. The main constituent of prions is PrPSc, an aggregated moiety of the host-derived membrane glycolipoprotein PrPC. Prions were found to encipher many phenotypic, genetically stable TSE variants. The latter is very surprising, since PrPC is encoded by the host genome and all prion strains share the same amino acid sequence. Here I will review what is known about the infectivity, the neurotoxicity, and the neuroinvasiveness of prions. Also, I will explain why I regard the prion strain question as a fascinating challenge – with implications that go well beyond prion science. Finally, I will report some recent results obtained in my laboratory, which is attempting to address the strain question and some other basic issues of prion biology with a “systems” approach that utilizes organic chemistry, photophysics, proteomics, and mouse transgenesis.