Diabetic nephropathy (DN) is a chronic complication of type 2 diabetes and is the most frequent form of chronic kidney disease that can lead to end-stage renal disease. Different pathways, involved in oxidative stress, inflammation, fibrosis and cell death, are responsible for the pathogenesis of DN and regulate the progression of the disease. Ubiquitination is a fundamental pathway in intracellular signaling whose role is emerging in the regulation of molecular processes responsible for several human diseases. Among the conventional ubiquitination pathway, leading to proteasomal degradation of proteins, also non-conventional ubiquitination plays an important role in the regulation of intracellular signaling. Several proteasome inhibitors have been developed and tested both in humans and in animal models and show potential as promising therapeutic approaches. In this review, we focused our attention on the role of ubiquitination pathway in the principal processes involved in the pathogenesis and progression of DN.