Systemic amyloid diseases are characterized by widespread protein deposition as amyloid fibrils. Precise diagnostic framing is the prerequisite for a correct management of patients. This complex process is achieved through a series of steps, which include detection of the tissue amyloid deposits, identification of the amyloid type, demonstration of the amyloidogenic precursor, and evaluation of organ dysfunction/damage. Laboratory medicine plays a central role in the diagnosis and management of systemic amyloidoses, through the quantification of the amyloidogenic precursor and evaluation of end-organ damage using biomarkers.