Far from being bystanders in diabetic nephropathy, changes in the proximal tubule are important for the development of progressive diabetic kidney disease. The proximal tubule is uniquely susceptible to a variety of metabolic and hemodynamic factors associated with diabetes. Renal function and prognosis correlate better with structural lesions in the tubuli and cortical interstitium than with classical glomerular changes of diabetic nephropathy. The proximal tubules show a variety of poorly characterized changes, which have led to the notion that tubular damage represents a "final common pathway" for proteinuric renal injury. However, tubular hypertrophy, reduced organic ion transport, and other tubular changes reviewed in this paper, are already apparent before the onset of proteinuria in diabetes. Indeed, increased tubuloglomerular feedback and defective uptake and lysosomal processing may independently contribute to hyperfiltration and urinary protein loss, respectively. This finding does not mean that glomerular or vascular dysfunction do not contribute to progressive nephropathy. However, although subdividing the nephron for the purposes of analysis and scientific discovery may be useful, the interactions between tubule, glomerulus, and interstitium are likely key to the understanding of complex disorders such as diabetic nephropathy. From this "holonephric" point of view, an understanding of the changes in the diabetic tubule forms an important component to the understanding of kidney disease in diabetes.