Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD). Approximately, one third of diabetic patients develop diabetic nephropathy. As diabetes and its associated metabolic diseases are becoming epidemic, DN is emerging as a major health threat to humans. Currently, there are no effective therapeutic treatments for the disease. As a result, most DN cases progress to ESRD; patients with ESRD will need to undergo renal replacement through either dialysis or kidney transplantation. Therefore, developing new and effective means to control DN has been a major focus in the diabetes research. DN is a complex disease with pathological changes occurred in the glomerulus and renal tubules. It is, nonetheless, widely believed that the primary defects lie in the glomeruli, which lead to disrupting the integrity of the glomerular filtration barrier. While a variety of factors contribute to the impairment of glomerular filtration function, a large body of evidence demonstrates that damage in podocytes is the leading cause. Renal fibrosis plays critical roles in promoting DN progression. The primary mechanism responsible for renal fibrosis is abnormal activation of the transforming growth factor (TGF)-β pathway. Based on this understanding of DN pathogenesis, one strategy to control DN is to specifically protect podocytes from diabetes-induced injuries and to inhibit TGF-β signaling using gene therapy methodology. In this review, we will discuss the current research effort in developing gene therapy for DN.