The proximal tubule (PT) reabsorbs filtered proteins via receptor mediated endocytosis to prevent energetically inefficient wasting in the urine. Recent intravital imaging studies have suggested that protein reabsorption occurs in early (S1) segments, which have a very high capacity. In contrast, uptake of fluid phase substrates also occurs in distal (S2) segments. In this article, we will review these findings and their implications for understanding integrated proximal tubular function, patterns of damage caused by endocytosed toxins, and the origins of proteinuria. We will also discuss whether compensatory downstream increases in protein uptake might occur in disease states, and the environmental factors that could drive these changes.