Urinary proteomics is a promising tool for biomarker investigation, particularly in complex kidney diseases. Fabris and colleagues report that urinary laminin subunit alpha-2 is a potential diagnostic marker of medullary sponge kidney (MSK) disease by using a label-free quantitative proteomics platform and a clinically compatible enzyme-linked immunosorbent assay. The neglected issue of stone pathogenesis was also evidenced. This commentary discusses several considerations in biomarker validation, and how urinary proteomics breaks new ground in MSK research.