AbstractLipocalin‐2 is a functional biomarker for acute and chronic kidney diseases, heart failure and obesity‐related medical complications. It is rapidly induced in epithelial cells under stress conditions, but constitutively produced from pre‐adipocytes and mature adipocytes. Measuring the lipocalin‐2 levels represents an effective approach for risk prediction, patient stratification and disease management. Nevertheless, due to ligand‐binding, post‐translational modification and protein‐protein interaction, lipocalin‐2 exists as multiple variants that elicit different pathophysiological functions. To characterize the specific structure‐functional relationships of lipocalin‐2 variants is critical for the development of biomarker assays with sufficient precision and reliability. Moreover, identifying the pathological forms of lipocalin‐2 will provide new therapeutic targets and treatment approaches for obesity‐related complications.