Transmissible spongiform encephalopathies (TSEs), or prion diseases, are neurodegenerative diseases that affect animals and humans, and being scrapie is the prototype disorder for this group of diseases. The specific mechanisms of pathogenesis associated with TSEs are not well understood. Genomic tools could assist in clarifying some of the molecular mechanisms of the associated pathology, comparing the transcriptional level between healthy and infected individuals. Moreover, it could allow the identification of molecules for diagnostic and for therapeutic targets in TSEs and other neurodegenerative diseases. So far, the studies developed have identified many potential biomarkers at the genetic level. These genes encode proteins involved in lipid metabolism, proteins having function of proteases, protease inhibitors and chaperones. However, the genes confirmed as specific biomarkers for TSEs are very few. Other molecular approaches, as proteomics, next generation sequencing or quantitative PCR, are used for the same purposes. In this study the results obtained so far are reviewed. The identification of new biomarkers associated with TSEs is still necessary, especially in the natural hosts of these diseases. Most studies have been conducted in mice as animal models of TSEs, but the knowledge of the genomes of natural hosts, such as ovine, makes possible the use of genomic tools in these species.