Introduction An important role of the kidney proximal tubule is to reabsorb glomerularly filtered peptides and proteins. This occurs by receptor-mediated uptake by two large multiligand endocytic receptors, megalin and cubilin, which are highly enriched on the apical surface of proximal tubule epithelial cells. The process is highly efficient as reflected by the fact that in the healthy kidney, urine is practically devoid of protein. However, kidney disease with glomerular injury increases the load of filtered plasma proteins, in particular albumin, leading to proteinuria.   Objectives Our objective is to understand the molecular basis of proximal tubule protein reabsorption and how it is regulated under normal and pathological conditions, with focus on the megalin and cubilin receptor system and its role in proteinuric disease.    Method In our studies, we use a variety of molecular and cellular techniques as well transgenic animal models, to investigate the renal handling of filtered proteins by the megalin and cubilin receptors.   Results Our research and that of co-workers has over the years established the essential role of the megalin and cubilin receptor system in modulating urinary protein excretion. Using a genetic model of glomerular kidney disease in combination with gene knockout of the receptors, we have further recently explored the implications of receptor dysfunction under nephrotic-range proteinuria. We observed massive albumin uptake in proximal tubules under nephrotic proteinuria, which was efficiently blocked by megalin and cubilin receptor knockout. In addition, we found evidence of potential distinct roles of the cubilin and megalin receptor in the uptake of albumin at normal filtered levels and nephrotic levels of albumin.   Conclusion Renal tubular reabsorption and rescue of filtered proteins, including albumin, is dependent on the megalin and cubilin receptors. Dysfunction of the receptors causes mild tubular proteinuria whereas glomerular kidney disease with increased filtration of plasma proteins overwhelms the receptors, causing nephrotic range proteinuria accompanied by massive protein uptake in the proximal tubules. These findings have implications for the pathophysiology and diagnosis of proteinuric renal diseases.   Ethics All animal experiments were performed in accordance with the EU Animal Welfare Act for humane treatment of vertebrate animals and licenses issued by the Danish Animal Experiments Inspectorate.