In both humans and animals, a group of transmissible neurodegenerative conditions has been observed which are not caused by classical infectious agents. These disorders include Creutzfeldt-Jakob-Disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats and chronic wasting disease (CWD) in cervids. The so-called prion diseases are primarily characterised by the accumulation of a proteinase-resistant protein (designated “prion”) that is an isoform of the endogenous prion protein, mainly expressed in the central nervous system. There are several indications which tasks the cellular prion protein might fulfil but its exact function has not yet been clarified. The pathogenesis of prion diseases is closely linked to the presence of the prion protein in a number of cell types, an association which has been explored by using transgenic mouse models. The basic event in prion propagation seems to be the transformation of the normal -helix rich isoform into another that is mainly composed of -sheets and differs from cellular prion protein in a number of biochemical properties. The ensuing accumulation and aggregation of this latter proteinase-resistant form leads to neurodegeneration. Several models have been proposed in order to explain aggregation. Genetic factors are known to play a considerable role in the conversion process by influencing the structural stability of the prion protein or otherwise its expression levels. Furthermore, interactions of the prion protein with other endogenous protein molecules may have an impact on pathogenesis and phenotype in prion diseases. This also applies to the species barrier, i.e. to transmissibility of the diseases between individuals or from one species to an other. The existence of several prion protein conformations and glycosylation patterns apparently leads to the development of multiple prion strains. Thus disease phenotype seems to be determined by the structure of both the endogenous prion protein and the infectious prion. Genetic factors are strongly associated with these aspects of prion disease as they have an effect on host prion protein conformation. This work outlines the fundamental features of prion diseases including the structural properties of the prion protein and the prion. Different models of prion aggregation are furthermore introduced with a special reference to genetic implications. In addition, the most common prion diseases of humans and animals are characterised and viewed in a genetic perspective. Putative candidate genes that may be associated with prion diseases are discussed together with mechanisms by which they might exert their influence.