Human prion diseases are rare neurodegenerative disorders related to prion protein misfolding that can occur as sporadic, familial or acquired forms. In comparison to other more common neurodegenerative disorders, prion diseases show a wider range of phenotypic variation and largely transmit to experimental animals, a feature that led to the isolation and characterization of different strains of the transmissible agent or prion with distinct biological properties. Biochemically distinct PrP(Sc) types have been demonstrated which differ in their size after proteinase cleavage, glycosylation pattern, and possibly other features related to their conformation. These PrP(Sc) types, possibly enciphering the prion strains, together with the naturally occurring polymorphism at codon 129 in the prion protein gene have a major influence on the disease phenotype. In the sporadic form, the most common but perhaps least understood form of human prion disease, there are at least six major combinations of codon 129 genotype and prion protein isotype, which are significantly related to distinctive clinical-pathological subgroups of the disease. In this review, we provide an update on the current knowledge and classification of the disease subtypes of the sporadic human prion diseases as defined by molecular features and pathological changes. Furthermore, we discuss the molecular basis of phenotypic variability taking into account the results of recent transmission studies that shed light on the extent of prion strain variation in humans.