In vitro and ex vivo studies have elucidated the step-by-step process whereby some physicochemically abnormal light chains are processed by mesangial cells to form amyloid fibrils. Although crucial steps in the cascade of events have been determined, these findings have not been reproduced in vivo. This has led to some doubts as to the significance and clinical application of the information that has been deciphered. Here, we developed an animal model which uses mice injected with amyloidogenic light chains purified from the urine of patients with biopsy-proven, light-chain-associated glomerular amyloidosis which validated in vitro/ex vivo findings. This animal model showed internalization of the light chains utilizing caveolae followed by trafficking to the mature lysosomal compartment where fibrils were formed. This model permits evaluation of mesangial amyloidogenesis for prolonged periods of time, is potentially useful to test maneuvers to modulate events that take place, and can be used to design novel therapeutic interventions.