Misfolding and aggregation of proteins are the main features of a group of diseases termed Protein Misfolding Disorders (PMDs). PMDs include Alzheimer's disease and Transmissible Spongiform Encephalopathies, among many others. The deposition of protein aggregates is the main responsible for tissue damage and the consequent clinical signs generated in such disorders. In this review, we will focus in the role of protein aggregates in these diseases and in the putative mechanisms by which they exert their toxicity.