Amyloidosis is not one entity but a grouping of disorders in all of which there is a tissue protein deposit with similar morphological, structural, and staining properties despite involving fundamentally different proteins or peptides. Each protein is involved in its own specific pathogenetic mechanism. These mechanisms determine, in a manner as yet unknown, which protein will be present in an amyloid deposit. The role of proteolysis in the pathogenesis is questioned. Proteolysis may well be a postfibrillogenic event. Local tissue factors, such as the basement membrane form of heparan sulfate proteoglycan, in addition to perhaps other basement membrane components, may play an important role in the genesis of amyloid. Differences, common themes, and various unanswered questions related to the pathogenesis of the amyloids are presented as are practical diagnostic considerations.