The epidemic of diabetic kidney disease is predicted to rise significantly in the next decade and will continue to represent the leading cause of end-stage renal failure. The interaction between metabolic and haemodynamic insults represents an important driver of the relentless decline in renal function that we observe in patients with diabetes. Studies have described different cellular pathophysiological mechanisms of diabetic glomerulopathy; increased oxidative stress appears to be the major alteration that drives the activation of many other cellular pathways which in turn will result in the phenotypic alterations seen in diabetic glomerulopathy. The glomerulus should be seen as a delicate network of cells that interact closely with one another in regulating the process of water and small solute filtration. In diabetes, this equilibrium is disrupted and its correction should aim at reinstating the balanced equilibrium as seen in physiology. Future therapeutic challenges will be represented by a tissue-specific personalized 'ad hoc' therapeutical approach which will depend on patients' characteristic and stage/progression of disease.