<b><i>Background:</i></b> The renal biopsy represents a cornerstone in the definition of monoclonal gammopathy of renal significance (MGRS), helping in identifying patients with sub-detectable neoplastic clones (MGUS) that would deserve aggressive chemotherapies. However, the rising complexity of this onco-nephrology field is significantly challenging the daily work of nephrologists and nephropathologists, leading to the formation of ultra-specialized international centers with dedicated personnel/instrumentation and stressing the need for a better understanding of the underlying molecular landscape of these entities. <b><i>Summary:</i></b> In this setting, the application of proteomic techniques, some with in situ capabilities (e.g., MALDI-MS imaging), for the investigation of the most challenging MGRS is progressively shedding light on the pathobiology of these diseases, providing new insights in the diagnosis and prognosis of these cases. This transformation is further enhanced by the application of next-generation digital pathology platforms, leading to a significant improvement of the cultural background for physicians thanks to second opinions, database and atlas creation, enhancement of diagnostic reports, with obvious repercussions for patients both in terms of turnaround time and appropriateness. <b><i>Key Messages:</i></b> The present review is aimed at bridging the gap between clinical questions (i.e., a better characterization of MGRS) and the molecular landscape of onco-nephrology entities.