Diagnostic workup of systemic AL amyloidosis. Systemic amyloidosis can be suspected on the basis of symptoms of organ involvement or during biomarker-based follow-up of monoclonal gammopathy of undetermined significance. Imaging is crucial in identifying heart involvement. The echocardiographic features of advanced cardiac amyloidosis are distinctive, with nondilated ventricles showing thickening of ventricular walls, as well as of interventricular and interatrial septa; amyloid infiltration gives a characteristic “granular sparkling” aspect to the myocardial texture. Cardiac magnetic resonance imaging shows global subendocardial late gadolinium enhancement and associated abnormal myocardial and blood-pool gadolinium kinetics. Equilibrium contrast magnetic resonance imaging allows quantification of the myocardial extracellular volume, which is related to amyloid load. Diagnosis is based on tissue biopsy. Less-invasive biopsy sites (abdominal fat, minor salivary glands) can be preferred. Amyloid deposits need to be characterized by reliable techniques to unequivocally identify amyloid type. Staging of organ dysfunction and characterization of the plasma cell clone offer guidance to the design of the therapeutic approach. CT, computed tomography; ECG, electrocardiogram; ECV, extracellular volume; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; iFISH, immunofluorescence in situ hybridization; MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging; PYP, pyrophosphate; US, ultrasound.