Systemic amyloid diseases are complex entities, in which an intricate interplay between multiple factors is responsible for protein misfolding and deposition, with consequent cell and organ dysfunction. The chapter provides an overview of major past and recent advancements in the study of the molecular bases of protein misfolding diseases. Many questions are still open, notably the molecular mechanisms underlying tissue targeting and organ dysfunction remain elusive. However, the use of a multidisciplinary approach has allowed making important steps towards the clarification of the pathogenic mechanisms, opening the way for the study of new targeted therapies. It is now clear that interactions with the environment, along with inherent biochemical and biophysical properties, determine the fate of an amyloidogenic protein in vivo. During the years, the concept of a direct toxicity of protein aggregates has emerged, and the pathogenic role of fibrils and prefibrillar species and the pathways through which the damage occurs have been objects of intense investigation, leading to a deeper—although not yet complete—understanding of the molecular events behind organ dysfunction and to the development of new paradigms in the treatment of systemic amyloidosis.