Rudolph Virchow, in 1854, introduced and popularized the term amyloid to denote a macroscopic tissue abnormality that exhibited a positive iodine staining reaction. Subsequent light microscopic studies with polarizing optics demonstrated the inherent birefringence of amyloid deposits, a property that increased intensely after staining with Congo red dye. In 1959, electron microscopic examination of ultrathin sections of amyloidotic tissues revealed the presence of fibrils, indeterminate in length and, invariably, 80 to 100 Angstrom in width. Using the criteria of Congophilia and fibrillar morphology, 20 or more biochemically distinct forms of amyloid have been identified throughout the animal kingdom; each is specifically associated with a unique clinical syndrome. Fibrils, also 80 to 100 A in width, have been isolated from tissue homogenates using differential sedimentation or solubility. X-ray diffraction analysis revealed the fibrils to be ordered in the beta pleated sheet conformation, with the direction of the polypeptide backbone perpendicular to the fibril axis (cross beta structure). Because of the similar dimensions and tinctorial properties of the fibrils extracted from amyloid-laden tissues and amyloid fibrils in tissue sections, they have been assumed to be identical. However, the spatial relationship of proteoglycans and amyloid P component (AP), common to all forms of amyloid, to the putative protein only fibrils in tissues, has been unclear. Recently, it has been suggested that, in situ, amyloid fibrils are composed of proteoglycans and AP as well as amyloid proteins and thus resemble connective tissue microfibrils. Chemical and physical definition of the fibrils in tissues will be needed to relate the in vitro properties of amyloid protein fibrils to the pathogenesis of amyloid fibril formation in vivo.