Ultrastructural labeling can play a key role in the evaluation of morphologic expressions of monoclonal light chain-related renal diseases in cases where light microscopy, electron microscopy, and immunofluorescence data, even when combined, are not definitive in conveying a diagnosis and, in other cases, in clarifying the findings by providing immuno-morphologic correlation. The important role of ultrastructural labeling is highlighted by the fact that in some of these cases bone marrow aspirates and biopsy specimens obtained at the time of the evaluation of the renal specimens are often unable to establish unequivocally a diagnosis of plasma cell dyscrasia. This is in part because renal manifestations commonly precede overt diagnostic bone marrow alterations. Overt bone marrow findings and clinical manifestations may be preceded for as long as 16 years by the renal manifestations. Determination or confirmation of monoclonality and detection of early deposition of monotypical light chains before the finding of ultrastructural morphologic correlates (ie, subendothelial, punctate, granular, electron-dense material) represent unique attributes of this technique. The increased sensitivity of ultra-structural immunolabeling compared with other available diagnostic techniques and its exquisite immunomorphologic correlative capabilities result in a comprehensive evaluation. Sixteen monoclonal light chain-related renal disease cases with early, unusual, or equivocal immunomorphologic manifestations that may have not been characterized properly if ultrastructural labeling had not been performed are presented. The crucial role played by ultrastructural labeling in evaluating these cases and establishing an accurate diagnosis is illustrated and emphasized. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.