Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein. About 23 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic structure although they are associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls, and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. This rarity and the variable involvement of different organs and tissues are often responsible for missed or delayed diagnosis, and amyloidosis remains a considerable clinical challenge. However, recent elucidation of important aspects of pathogenesis, as well as developments in diagnosis, monitoring, and treatment, have greatly improved outcomes, especially when patients are managed in specialist centers.